Dual magl and faah inhibitors

ABSTRACT

Provided herein are compounds and pharmaceutical compositions comprising said compounds useful as modulators of MAGL and/or FAAH. The subject compounds and compositions are useful for the treatment of pain and neurological disorders.

CROSS-REFERENCE

This application claims benefit of U.S. Provisional Application No.62/470,830, filed on Mar. 13, 2017, which is herein incorporated byreference in its entirety.

BACKGROUND OF THE INVENTION

Monoacylglycerol lipase (MAGL) is an enzyme responsible for hydrolyzingendocannabinoids such as 2-AG (2-arachidonoylglycerol), an arachidonatebased lipid, in the nervous system. Fatty acid amide hydrolase (FAAH) isanother enzyme responsible for hydrolyzing endocannabinoids such asanandamide.

BRIEF SUMMARY OF THE INVENTION

This disclosure provides, for example, compounds and compositions whichare modulators of MAGL and/or FAAH, and their use as medicinal agents,processes for their preparation, and pharmaceutical compositions thatinclude disclosed compounds as at least one active ingredient. Thedisclosure also provides for the use of disclosed compounds asmedicaments and/or in the manufacture of medicaments for the inhibitionof MAGL, and/or FAAH, activity in warm-blooded animals such as humans.

In some embodiments is a compound of Formula (I):

wherein:

-   each R¹ is independently selected from halogen, —CN, C₁₋₆alkyl,    C₂₋₆alkynyl, C₁₋₆alkyl-OR⁷, C₁₋₆haloalkyl, C₃₋₈cycloalkyl, —NR⁵R⁶,    —C(O)NR⁵R⁶, —SO₂R¹², —SF₅, —SR⁸, aryl, and heteroaryl, wherein aryl    and heteroaryl are optionally substituted with one or two groups    independently selected from halogen, C₁₋₆alkyl, C₁₋₆haloalkyl, and    —C(O)NR⁸R⁹; or two adjacent R¹ form a heterocycloalkyl ring    optionally substituted with one or two R¹¹;-   R² is C₁₋₆alkyl;-   R³ is selected from halogen, —CN, C₁₋₆alkyl, C₁₋₆haloalkyl, —NR⁸R⁹,    —C(O)NR⁸R⁹, —NR⁸C(O)R⁹, and —NR⁹SO₂R⁸;-   R^(3a) is selected from halogen, C₁₋₆alkyl, and C₁₋₆haloalkyl;-   each R⁴ is independently selected from H and C₁₋₆alkyl;-   each R⁵ and R⁶ is independently selected from H, C₁₋₆alkyl, and    C₃₋₈cycloalkyl; or R⁵ and R⁶, together with the nitrogen to which    they are attached, form a heterocycloalkyl optionally substituted    with one or two R¹⁰;-   each R⁷ is independently selected from H, C₁₋₆alkyl,    C₁₋₆alkyl-O—C₁₋₆alkyl, C₁₋₆haloalkyl, C₃₋₈cycloalkyl,    heterocycloalkyl, aryl, and heteroaryl, wherein heterocycloalkyl,    aryl, and heteroaryl are optionally substituted with one or two    groups independently selected from halogen, C₁₋₆alkyl, and    C₁₋₆haloalkyl;-   each R⁸ and R⁹ is independently selected from H, C₁₋₆alkyl,    C₃₋₈cycloalkyl, aryl, and heteroaryl;-   each R¹⁰ is independently selected from C₁₋₆alkyl, C₃₋₈cycloalkyl,    C₁₋₆haloalkyl, halogen, oxo, —CN, —C(O)OR⁸, —C(O)R⁸, —C(O)NR⁸R⁹,    —SO₂R⁸, —NR⁹C(O)R⁸, and —NR⁹SO₂R⁸;-   each R¹¹ is independently selected from halogen and C₁₋₆alkyl;-   each R¹² is independently selected from C₁₋₆alkyl and    C₃₋₈cycloalkyl;-   m is 0, 1, 2, 3, 4, or 5;-   n is 0, 1, 2, or 3;-   p is 0 or 1; and-   q is 0 or 1;    or a pharmaceutically acceptable salt, solvate, or stereoisomer    thereof.

In some embodiments is a compound of Formula (I), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein R⁴ is H.

In some embodiments is a compound of Formula (II):

wherein:

-   each R¹ is independently selected from halogen, —CN, C₁₋₆alkyl,    C₂₋₆alkynyl, C₁₋₆alkyl-OR⁷, C₁₋₆haloalkyl, C₃₋₈cycloalkyl, —NR⁵R⁶,    —C(O)NR⁵R⁶, —OR⁷, —SO₂R¹², —SF₅, —SR⁸, aryl, and heteroaryl, wherein    aryl and heteroaryl are optionally substituted with one or two    groups independently selected from halogen, C₁₋₆alkyl,    C₁₋₆haloalkyl, and —C(O)NR⁸R⁹; or two adjacent R¹ form a    heterocycloalkyl ring optionally substituted with one or two R¹¹;-   R² is C₁₋₆alkyl;-   R³ is selected from halogen, —CN, C₁₋₆alkyl, C₁₋₆haloalkyl, —NR⁸R⁹,    —C(O)NR⁸R⁹, —NR⁸C(O)R⁹, and —NR⁹SO₂R⁸;-   R^(3a) is selected from halogen, C₁₋₆alkyl, and C₁₋₆haloalkyl;-   each R⁵ and R⁶ is independently selected from H, C₁₋₆alkyl, and    C₃₋₈cycloalkyl; or R⁵ and R⁶, together with the nitrogen to which    they are attached, form a heterocycloalkyl optionally substituted    with one or two R¹⁰;-   each R⁷ is independently selected from H, C₁₋₆alkyl,    C₁₋₆alkyl-O—C₁₋₆alkyl, C₁₋₆haloalkyl, C₃₋₈cycloalkyl,    heterocycloalkyl, aryl, and heteroaryl, wherein heterocycloalkyl,    aryl, and heteroaryl are optionally substituted with one or two    groups independently selected from halogen, C₁₋₆alkyl, and    C₁₋₆haloalkyl;-   each R⁸ and R⁹ is independently selected from H, C₁₋₆alkyl,    C₃₋₈cycloalkyl, aryl, and heteroaryl;-   each R¹⁰ is independently selected from C₁₋₆alkyl, C₃₋₈cycloalkyl,    C₁₋₆haloalkyl, halogen, oxo, —CN, —C(O)OR⁸, —C(O)R⁸, —C(O)NR⁸R⁹,    —SO₂R⁸, —NR⁹C(O)R⁸, and —NR⁹SO₂R⁸;-   each R¹¹ is independently selected from halogen and C₁₋₆alkyl;-   each R¹² is independently selected from C₁₋₆alkyl and    C₃₋₈cycloalkyl;-   m is 0, 1, 2, 3, 4, or 5;-   n is 0, 1, 2, or 3;-   p is 0 or 1; and-   q is 0 or 1;    or a pharmaceutically acceptable salt, solvate, or stereoisomer    thereof.

In some embodiments is a compound of Formula (I) or (II), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein p is 0. In some embodiments is a compound of Formula (I) or(II), or a pharmaceutically acceptable salt, solvate, or stereoisomerthereof, wherein p is 1. In some embodiments is a compound of Formula(I) or (II), or a pharmaceutically acceptable salt, solvate, orstereoisomer thereof, wherein R² is C₁₋₆alkyl. In some embodiments is acompound of Formula (I) or (II), or a pharmaceutically acceptable salt,solvate, or stereoisomer thereof, wherein R² is —CH3. In someembodiments is a compound of Formula (I) or (II), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein

In some embodiments is a compound of Formula (I) or (II), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein

In some embodiments is a compound of

Formula (I) or (II), or a pharmaceutically acceptable salt, solvate, orstereoisomer thereof, wherein

In some embodiments is a compound of Formula (I) or (II), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein n is 1. In some embodiments is a compound of Formula (I) or(II), or a pharmaceutically acceptable salt, solvate, or stereoisomerthereof, wherein

In some embodiments is a compound of Formula (III):

wherein:

-   each R¹ is independently selected from halogen, —CN, C₁₋₆alkyl,    C₂₋₆alkynyl, C₁₋₆alkyl-OR⁷, C₁₋₆haloalkyl, C₃₋₈cycloalkyl, —NR⁵R⁶,    —C(O)NR⁵R⁶, —OR⁷, —SO₂R¹², —SF₅, —SR⁸, aryl, and heteroaryl, wherein    aryl and heteroaryl are optionally substituted with one or two    groups independently selected from halogen, C₁₋₆alkyl,    C₁₋₆haloalkyl, and —C(O)NR⁸R⁹; or two adjacent R¹ form a    heterocycloalkyl ring optionally substituted with one or two R¹¹;-   R³ is selected from halogen, —CN, C₁₋₆alkyl, C₁₋₆haloalkyl, —NR⁸R⁹,    —C(O)NR⁸R⁹, —NR⁸C(O)R⁹, and —NR⁹SO₂R⁸;-   R^(3a) is selected from halogen, C₁₋₆alkyl, and C₁₋₆haloalkyl;-   each R⁵ and R⁶ is independently selected from H, C₁₋₆alkyl, and    C₃₋₈cycloalkyl; or R⁵ and R⁶, together with the nitrogen to which    they are attached, form a heterocycloalkyl optionally substituted    with one or two R¹⁰;-   each R⁷ is independently selected from H, C₁₋₆alkyl,    C₁₋₆alkyl-O—C₁₋₆alkyl, C₁₋₆haloalkyl, C₃₋₈cycloalkyl,    heterocycloalkyl, aryl, and heteroaryl, wherein heterocycloalkyl,    aryl, and heteroaryl are optionally substituted with one or two    groups independently selected from halogen, C₁₋₆alkyl, and    C₁₋₆haloalkyl;-   each R⁸ and R⁹ is independently selected from H, C₁₋₆alkyl,    C₃₋₈cycloalkyl, aryl, and heteroaryl;-   each R¹⁰ is independently selected from C₁₋₆alkyl, C₃₋₈cycloalkyl,    C₁₋₆haloalkyl, halogen, oxo, —CN, —C(O)OR⁸, —C(O)R⁸, —C(O)NR⁸R⁹,    —SO₂R⁸, —NR⁹C(O)R⁸, and —NR⁹SO₂R⁸;-   each R¹¹ is independently selected from halogen and C₁₋₆alkyl;-   each R¹² is independently selected from C₁₋₆alkyl and    C₃₋₈cycloalkyl;-   m is 0, 1, 2, 3, 4, or 5;-   q is 0 or 1;-   w is 1 or 2;-   x is 0 or 1;-   y is 0 or 1; and-   z is 0 or 1;    wherein when y and z are 0, then x is 1 and w is 2;    when y and z are 1, then w is 1; and    when y is 1 and z is 0, or y is 0 and z is 1, then x is 1;    or a pharmaceutically acceptable salt, solvate, or stereoisomer    thereof.

In some embodiments is a compound of Formula (III) having the structureof Formula (IIIa):

In some embodiments is a compound of Formula (III) having the structureof Formula (IIIb):

In some embodiments is a compound of Formula (IV):

wherein:

-   each R¹ is independently selected from halogen, —CN, C₁₋₆alkyl,    C₂₋₆alkynyl, C₁₋₆alkyl-OR⁷, C₁₋₆haloalkyl, C₃₋₈cycloalkyl, —NR⁵R⁶,    —C(O)NR⁵R⁶, —OR⁷, —SO₂R¹², —SF₅, —SR⁸, aryl, and heteroaryl, wherein    aryl and heteroaryl are optionally substituted with one or two    groups independently selected from halogen, C₁₋₆alkyl,    C₁₋₆haloalkyl, and —C(O)NR⁸R⁹; or two adjacent R¹ form a    heterocycloalkyl ring optionally substituted with one or two R¹¹;-   R³ is selected from halogen, —CN, C₁₋₆alkyl, C₁₋₆haloalkyl, —NR⁸R⁹,    —C(O)NR⁸R⁹, —NR⁸C(O)R⁹, and —NR⁹SO₂R⁸;-   R^(3a) is selected from halogen, C₁₋₆alkyl, and C₁₋₆haloalkyl;-   each R⁵ and R⁶ is independently selected from H, C₁₋₆alkyl, and    C₃₋₈cycloalkyl; or R⁵ and R⁶, together with the nitrogen to which    they are attached, form a heterocycloalkyl optionally substituted    with one or two R¹⁰;-   each R⁷ is independently selected from H, C₁₋₆alkyl,    C₁₋₆alkyl-O—C₁₋₆alkyl, C₁₋₆haloalkyl, C₃₋₈cycloalkyl,    heterocycloalkyl, aryl, and heteroaryl, wherein heterocycloalkyl,    aryl, and heteroaryl are optionally substituted with one or two    groups independently selected from halogen, C₁₋₆alkyl, and    C₁₋₆haloalkyl;-   each R⁸ and R⁹ is independently selected from H, C₁₋₆alkyl,    C₃₋₈cycloalkyl, aryl, and heteroaryl;-   each R¹⁰ is independently selected from C₁₋₆alkyl, C₃₋₈cycloalkyl,    C₁₋₆haloalkyl, halogen, oxo, —CN, —C(O)OR⁸, —C(O)R⁸, —C(O)NR⁸R⁹,    —SO₂R⁸, —NR⁹C(O)R⁸, and —NR⁹SO₂R⁸;-   each R¹¹ is independently selected from halogen and C₁₋₆alkyl;-   each R¹² is independently selected from C₁₋₆alkyl and    C₃₋₈cycloalkyl;-   m is 0, 1, 2, 3, 4, or 5; and-   q is 0 or 1;    or a pharmaceutically acceptable salt, solvate, or stereoisomer    thereof.

In some embodiments is a compound of Formula (I), (II), (III), (IIIa),(IIIb), or (IV), or a pharmaceutically acceptable salt, solvate, orstereoisomer thereof, wherein m is 1. In some embodiments is a compoundof Formula (I), (II), (III), (IIIa), (IIIb), or (IV), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein m is 2. In some embodiments is a compound of Formula (I), (II),(III), (IIIa), (IIIb), or (IV), or a pharmaceutically acceptable salt,solvate, or stereoisomer thereof, wherein R³ is C₁₋₆haloalkyl. In someembodiments is a compound of Formula (I), (II), (III), (IIIa), (IIIb),or (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomerthereof, wherein R³ is —CF₃. In some embodiments is a compound ofFormula (I), (II), (III), (IIIa), (IIIb), or (IV), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein R³ ishalogen. In some embodiments is a compound of Formula (I), (II), (III),(IIIa), (IIIb), or (IV), or a pharmaceutically acceptable salt, solvate,or stereoisomer thereof, wherein R³ is —C(O)NH₂. In some embodiments isa compound of Formula (I), (II), (III), (IIIa), (IIIb), or (IV), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein R³ is —CN. In some embodiments is a compound of Formula (I),(II), (III), (IIIa), (IIIb), or (IV), or a pharmaceutically acceptablesalt, solvate, or stereoisomer thereof, wherein q is 0. In someembodiments is a compound of Formula (I), (II), (III), (IIIa), (IIIb),or (IV), or a pharmaceutically acceptable salt, solvate, or stereoisomerthereof, wherein q is 1. In some embodiments is a compound of Formula(I), (II), (III), (IIIa), (IIIb), or (IV), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein each R¹ isindependently selected from halogen, —CN, C₁₋₆alkyl, C₁₋₆haloalkyl,—NR⁵R⁶, —OR⁷, and heteroaryl. In some embodiments is a compound ofFormula (I), (II), (III), (IIIa), (IIIb), or (IV), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein each R¹ isindependently selected from halogen, C₁₋₆haloalkyl, —NR⁵R⁶, and —OR⁷. Insome embodiments is a compound of Formula (I), (II), (III), (IIIa),(IIIb), or (IV), or a pharmaceutically acceptable salt, solvate, orstereoisomer thereof, wherein R⁵ and R⁶, together with the nitrogen towhich they are attached, form a heterocycloalkyl optionally substitutedwith one or two R¹⁰. In some embodiments is a compound of Formula (I),(II), (III), (IIIa), (IIIb), or (IV), or a pharmaceutically acceptablesalt, solvate, or stereoisomer thereof, wherein R⁵ and R⁶, together withthe nitrogen to which they are attached, form a heterocycloalkylsubstituted with one or two R¹⁰ independently selected from C₁₋₆alkyland —C(O)NR⁸R⁹. In some embodiments is a compound of Formula (I), (II),(III), (IIIa), (IIIb), or (IV), or a pharmaceutically acceptable salt,solvate, or stereoisomer thereof, wherein R⁵ and R⁶, together with thenitrogen to which they are attached, form an unsubstitutedheterocycloalkyl. In some embodiments is a compound of Formula (I),(II), (III), (IIIa), (IIIb), or (IV), or a pharmaceutically acceptablesalt, solvate, or stereoisomer thereof, wherein R⁵ and R⁶, together withthe nitrogen to which they are attached, form a heterocycloalkylselected from:

In some embodiments is a compound of Formula (I), (II), (III), (IIIa),(IIIb), or (IV), or a pharmaceutically acceptable salt, solvate, orstereoisomer thereof, wherein each R¹ is independently selected fromhalogen, C₁₋₆alkyl, C₁₋₆haloalkyl, and —OR⁷. In some embodiments is acompound of Formula (I), (II), (III), (IIIa), (IIIb), or (IV), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein each R⁷ is independently selected from C₁₋₆alkyl, C₁₋₆haloalkyl,C₃₋₈cycloalkyl, aryl, and heteroaryl. In some embodiments is a compoundof Formula (I), (II), (III), (IIIa), (IIIb), or (IV), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein each R⁷ is independently selected from C₁₋₆alkyl, C₁₋₆haloalkyl,and aryl. In some embodiments is a compound of Formula (I), (II), (III),(IIIa), (IIIb), or (IV), or a pharmaceutically acceptable salt, solvate,or stereoisomer thereof, wherein two adjacent R¹ form a heterocycloalkylring optionally substituted with one or two R¹¹. In some embodiments isa compound of Formula (I), (II), (III), (IIIa), (IIIb), or (IV), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein two adjacent R¹ form a heterocycloalkyl ring optionallysubstituted with one or two and each is independently selected fromhalogen.

In another embodiment is a pharmaceutical composition comprising acompound of Formula (I), (II), (III), (IIIa), (IIIb), or (IV) describedherein, or a pharmaceutically acceptable salt, solvate, or stereoisomerthereof, and at least one pharmaceutically acceptable excipient.

In another embodiment is a method of treating pain in a patient in needthereof, comprising administering to the patient a therapeuticallyeffective amount of a compound of Formula (I), (II), (III), (IIIa),(IIIb), or (IV) described herein, or a pharmaceutically acceptable salt,solvate, or stereoisomer thereof.

In another embodiment is a method of treating a neurological disorder ina patient in need thereof, comprising administering to the patient atherapeutically effective amount of a compound of Formula (I), (II),(III), (IIIa), (IIIb), or (IV) described herein, or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof.

DETAILED DESCRIPTION OF THE INVENTION

This disclosure is directed, at least in part, to modulators orinhibitors of MAGL and/or FAAH. For example, provided herein arecompounds capable of inhibiting MAGL and/or FAAH. In some embodiments,the compounds described herein are dual inhibitors capable of inhibitingMAGL and FAAH.

As used herein and in the appended claims, the singular forms “a,”“and,” and “the” include plural referents unless the context clearlydictates otherwise. Thus, for example, reference to “an agent” includesa plurality of such agents, and reference to “the cell” includesreference to one or more cells (or to a plurality of cells) andequivalents thereof. When ranges are used herein for physicalproperties, such as molecular weight, or chemical properties, such aschemical formulae, all combinations and subcombinations of ranges andspecific embodiments therein are intended to be included. The term“about” when referring to a number or a numerical range means that thenumber or numerical range referred to is an approximation withinexperimental variability (or within statistical experimental error), andthus the number or numerical range varies between 1% and 15% of thestated number or numerical range. The term “comprising” (and relatedterms such as “comprise” or “comprises” or “having” or “including”) isnot intended to exclude that which in other certain embodiments, forexample, an embodiment of any composition of matter, composition,method, or process, or the like, described herein, may “consist of” or“consist essentially of” the described features.

Definitions

As used in the specification and appended claims, unless specified tothe contrary, the following terms have the meaning indicated below.

As used herein, C₁-C_(x) includes C₁-C₂, C₁-C₃ . . . C₁-C_(x). C₁-C_(x)refers to the number of carbon atoms that make up the moiety to which itdesignates (excluding optional substituents).

“Amino” refers to the —NH₂ radical.

“Cyano” refers to the —CN radical.

“Nitro” refers to the —NO₂ radical.

“Oxa” refers to the —O— radical.

“Oxo” refers to the ═O radical.

“Thioxo” refers to the ═S radical.

“Imino” refers to the ═N—H radical.

“Oximo” refers to the ═N—OH radical.

“Alkyl” or “alkylene” refers to a straight or branched hydrocarbon chainradical consisting solely of carbon and hydrogen atoms, containing nounsaturation, having from one to fifteen carbon atoms (e.g., C₁-C₁₅alkyl). In certain embodiments, an alkyl comprises one to thirteencarbon atoms (e.g., C₁-C₁₃ alkyl). In certain embodiments, an alkylcomprises one to eight carbon atoms (e.g., C₁-C₈ alkyl). In otherembodiments, an alkyl comprises one to six carbon atoms (e.g., C₁-C₆alkyl). In other embodiments, an alkyl comprises one to five carbonatoms (e.g., C₁-C₅ alkyl). In other embodiments, an alkyl comprises oneto four carbon atoms (e.g., C₁-C₄ alkyl). In other embodiments, an alkylcomprises one to three carbon atoms (e.g., C₁-C₃ alkyl). In otherembodiments, an alkyl comprises one to two carbon atoms (e.g., C₁-C₂alkyl). In other embodiments, an alkyl comprises one carbon atom (e.g.,C₁ alkyl). In other embodiments, an alkyl comprises five to fifteencarbon atoms (e.g., C₅-C₁₅ alkyl). In other embodiments, an alkylcomprises five to eight carbon atoms (e.g., C₅-C₈ alkyl). In otherembodiments, an alkyl comprises two to five carbon atoms (e.g., C₂-C₅alkyl). In other embodiments, an alkyl comprises three to five carbonatoms (e.g., C₃-C₅ alkyl). In other embodiments, the alkyl group isselected from methyl, ethyl, 1-propyl (n-propyl), 1-methylethyl(iso-propyl), 1-butyl (n-butyl), 1-methylpropyl (sec-butyl),2-methylpropyl (iso-butyl), 1,1-dimethylethyl (tert-butyl), and 1-pentyl(n-pentyl). The alkyl is attached to the rest of the molecule by asingle bond. Unless stated otherwise specifically in the specification,an alkyl group is optionally substituted by one or more of the followingsubstituents: halo, cyano, nitro, oxo, thioxo, imino, oximo,trimethylsilanyl, —OR^(a), —SR^(a), —OC(O)R^(a), —N(R^(a))₂, —C(O)R^(a),—C(O)OR^(a), —C(O)N(R^(a))₂, —N(R^(a))C(O)OR^(f), —OC(O)—NR^(a)R^(f),—N(R^(a))C(O)R^(f), —N(R^(a))S(O)_(t)R^(f) (where t is 1 or 2),—S(O)_(t)OR^(a) (where t is 1 or 2), —S(O)_(t)R^(f) (where t is 1 or 2),and —S(O)_(t)N(R^(a))₂ (where t is 1 or 2), where each R^(a) isindependently hydrogen, alkyl, fluoroalkyl, cycloalkyl, aryl, aralkyl,heterocycloalkyl, heteroaryl, or heteroarylalkyl, and each R^(f) isindependently alkyl, fluoroalkyl, cycloalkyl, aryl, aralkyl,heterocycloalkyl, heteroaryl, or heteroarylalkyl.

“Alkoxy” refers to a radical bonded through an oxygen atom of theformula —O-alkyl, where alkyl is an alkyl chain as defined above.

“Alkenyl” refers to a straight or branched hydrocarbon chain radicalgroup consisting solely of carbon and hydrogen atoms, containing atleast one carbon-carbon double bond, and having from two to twelvecarbon atoms. In certain embodiments, an alkenyl comprises two to eightcarbon atoms. In other embodiments, an alkenyl comprises two to fourcarbon atoms. The alkenyl is attached to the rest of the molecule by asingle bond, for example, ethenyl (i.e., vinyl), prop-1-enyl (i.e.,allyl), but-1-enyl, pent-1-enyl, penta-1,4-dienyl, and the like. Unlessstated otherwise specifically in the specification, an alkenyl group isoptionally substituted by one or more of the following substituents:halo, cyano, nitro, oxo, thioxo, imino, oximo, trimethylsilanyl,—OR^(a), —SR^(a), —OC(O)—R^(f), —N(R^(a))₂, —C(O)R^(a), —C(O)OR^(a),—C(O)N(R^(a))₂, —N(R^(a))C(O)OR^(f), —OC(O)—NR^(a)R^(f), —N(R^(a))C(O)R^(f), —N(R^(a))S(O)_(t)R^(f) (where t is 1 or 2), —S(O)_(t)OR^(a)(where t is 1 or 2), —S(O)_(t)R^(f) (where t is 1 or 2), and—S(O)_(t)N(R^(a))₂ (where t is 1 or 2), where each R^(a) isindependently hydrogen, alkyl, fluoroalkyl, cycloalkyl, aryl, aralkyl,heterocycloalkyl, heteroaryl, or heteroarylalkyl, and each R^(f) isindependently alkyl, fluoroalkyl, cycloalkyl, aryl, aralkyl,heterocycloalkyl, heteroaryl, or heteroarylalkyl.

“Alkynyl” refers to a straight or branched hydrocarbon chain radicalgroup consisting solely of carbon and hydrogen atoms, containing atleast one carbon-carbon triple bond, having from two to twelve carbonatoms. In certain embodiments, an alkynyl comprises two to eight carbonatoms. In other embodiments, an alkynyl has two to four carbon atoms.The alkynyl is attached to the rest of the molecule by a single bond,for example, ethynyl, propynyl, butynyl, pentynyl, hexynyl, and thelike. Unless stated otherwise specifically in the specification, analkynyl group is optionally substituted by one or more of the followingsubstituents: halo, cyano, nitro, oxo, thioxo, imino, oximo,trimethylsilanyl, —OR^(a), —SR^(a), —OC(O)R^(a), —N(R^(a))₂, —C(O)R^(a),—C(O)OR^(a), —C(O)N(R^(a))₂, —N(R^(a))C(O)OR^(f), —OC(O)—NR^(a)R^(f),—N(R^(a))C(O)R^(f), —N(R^(a))S(O)_(t)R^(f) (where t is 1 or 2),—S(O)_(t)OR^(a) (where t is 1 or 2), —S(O)_(t)R^(f) (where t is 1 or 2),and —S(O)_(t)N(R^(a))₂ (where t is 1 or 2), where each R^(a) isindependently hydrogen, alkyl, fluoroalkyl, cycloalkyl, aryl, aralkyl,heterocycloalkyl, heteroaryl, or heteroarylalkyl, and each R^(f) isindependently alkyl, fluoroalkyl, cycloalkyl, aryl, aralkyl,heterocycloalkyl, heteroaryl, or heteroarylalkyl.

“Aryl” refers to a radical derived from an aromatic monocyclic ormulticyclic hydrocarbon ring system by removing a hydrogen atom from aring carbon atom. The aromatic monocyclic or multicyclic hydrocarbonring system contains only hydrogen and carbon from six to eighteencarbon atoms, where at least one of the rings in the ring system isfully unsaturated, i.e., it contains a cyclic, delocalized (4n+2)π-electron system in accordance with the Hückel theory. The ring systemfrom which aryl groups are derived include, but are not limited to,groups such as benzene, fluorene, indane, indene, tetralin, andnaphthalene. Unless stated otherwise specifically in the specification,the term “aryl” or the prefix “ar-” (such as in “aralkyl”) is meant toinclude aryl radicals optionally substituted by one or more substituentsindependently selected from alkyl, alkenyl, alkynyl, halo, fluoroalkyl,cyano, nitro, aryl, aralkyl, aralkenyl, aralkynyl, cycloalkyl,heterocycloalkyl, heteroaryl, heteroarylalkyl, —R^(b)—OR^(a),—R^(b)—OC(O)—R^(a), —R^(b)—OC(O)—OR^(a), —R^(b)—OC(O)—N(R^(a))₂,—R^(b)—N(R^(a))₂, —R^(b)—C(O) R^(a), —R^(b)—C(O)OR^(a),—R^(b)—C(O)N(R^(a))₂, —R^(b)—O—R^(c)—C(O)N(R^(a))₂,—R^(b)—N(R^(a))C(O)OR^(a), —R^(b)—N(R^(a))C(O)R^(a),—R^(b)—N(R^(a))S(O)_(t)R^(a) (where t is 1 or 2), —R^(b)—S(O)_(t)OR^(a)(where t is 1 or 2), —R^(b)—S(O)_(t)R^(a) (where t is 1 or 2) and—R^(b)—S(O)_(t)N(R^(a))₂ (where t is 1 or 2), where each R^(a) isindependently hydrogen, alkyl, fluoroalkyl, cycloalkyl, cycloalkylalkyl,aryl (optionally substituted with one or more halo groups), aralkyl,heterocycloalkyl, heteroaryl or heteroarylalkyl, each R^(b) isindependently a direct bond or a straight or branched alkylene oralkenylene chain, and R^(c) is a straight or branched alkylene oralkenylene chain.

“Aryloxy” refers to a radical bonded through an oxygen atom of theformula —O-aryl, where aryl is as defined above.

“Aralkyl” refers to a radical of the formula —R^(c)-aryl where Re is analkylene chain as defined above, for example, methylene, ethylene, andthe like. The alkylene chain part of the aralkyl radical is optionallysubstituted as described above for an alkylene chain. The aryl part ofthe aralkyl radical is optionally substituted as described above for anaryl group.

“Aralkyloxy” refers to a radical bonded through an oxygen atom of theformula —O-aralkyl, where aralkyl is as defined above.

“Aralkenyl” refers to a radical of the formula —R^(d)-aryl where R^(d)is an alkenylene chain as defined above. The aryl part of the aralkenylradical is optionally substituted as described above for an aryl group.The alkenylene chain part of the aralkenyl radical is optionallysubstituted as defined above for an alkenylene group.

“Aralkynyl” refers to a radical of the formula —Re-aryl, where Re is analkynylene chain as defined above. The aryl part of the aralkynylradical is optionally substituted as described above for an aryl group.The alkynylene chain part of the aralkynyl radical is optionallysubstituted as defined above for an alkynylene chain.

“Cycloalkyl” refers to a stable non-aromatic monocyclic or polycyclichydrocarbon radical consisting solely of carbon and hydrogen atoms,which includes fused or bridged ring systems, having from three tofifteen carbon atoms. In certain embodiments, a cycloalkyl comprisesthree to ten carbon atoms. In other embodiments, a cycloalkyl comprisesfive to seven carbon atoms. The cycloalkyl is attached to the rest ofthe molecule by a single bond. Cycloalkyls are saturated, (i.e.,containing single C—C bonds only) or partially unsaturated (i.e.,containing one or more double bonds or triple bonds.) Examples ofmonocyclic cycloalkyls include, e.g., cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, cycloheptyl, and cyclooctyl. In certainembodiments, a cycloalkyl comprises three to eight carbon atoms (e.g.,C₃-C₈ cycloalkyl). In other embodiments, a cycloalkyl comprises three toseven carbon atoms (e.g., C₃-C₇ cycloalkyl). In other embodiments, acycloalkyl comprises three to six carbon atoms (e.g., C₃-C₆ cycloalkyl).In other embodiments, a cycloalkyl comprises three to five carbon atoms(e.g., C₃-C₅ cycloalkyl). In other embodiments, a cycloalkyl comprisesthree to four carbon atoms (e.g., C₃-C₄ cycloalkyl). A partiallyunsaturated cycloalkyl is also referred to as “cycloalkenyl.” Examplesof monocyclic cycloalkenyls include, e.g., cyclopentenyl, cyclohexenyl,cycloheptenyl, and cyclooctenyl. Polycyclic cycloalkyl radicals include,for example, adamantyl, norbornyl (i.e., bicyclo[2.2.1]heptanyl),norbornenyl, decalinyl, 7,7-dimethyl-bicyclo[2.2.1]heptanyl, and thelike. Unless otherwise stated specifically in the specification, theterm “cycloalkyl” is meant to include cycloalkyl radicals optionallysubstituted by one or more substituents independently selected fromalkyl, alkenyl, alkynyl, halo, fluoroalkyl, cyano, nitro, aryl, aralkyl,aralkenyl, aralkynyl, cycloalkyl, heterocycloalkyl, heteroaryl,heteroarylalkyl, —R^(b)—OC(O)—R^(a), —R^(b)—OC(O)—OR^(a),—R^(b)—OC(O)—N(R^(a))₂, —R^(b)—N(R^(a))₂, —R^(b)—C(O)R^(a)—R^(b)—C(O)OR^(a), —R^(b)—C(O)N(R^(a))₂,—R^(b)—O—R^(c)—C(O)N(R^(a))₂, —R^(b)—N(R^(a))C(O)OR^(a),—R^(b)—N(R^(a))C(O)R^(a), —R^(b)—N(R^(a))S(O)_(t)R^(a) (where t is 1 or2), —R^(b)—S(O)_(t)OR^(a) (where t is 1 or 2), —R^(b)—S(O)_(t)R^(a)(where t is 1 or 2) and —R^(b)—S(O)_(t)N(R^(a))₂ (where t is 1 or 2),where each R^(a) is independently hydrogen, alkyl, fluoroalkyl,cycloalkyl, cycloalkylalkyl, aryl (optionally substituted with one ormore halo groups), aralkyl, heterocycloalkyl, heteroaryl orheteroarylalkyl, each R^(b) is independently a direct bond or a straightor branched alkylene or alkenylene chain, and R^(c) is a straight orbranched alkylene or alkenylene chain.

“Halo” or “halogen” refers to bromo, chloro, fluoro, or iodosubstituents.

“Haloalkyl” refers to an alkyl radical, as defined above, that issubstituted by one or more halo radicals, as defined above.

“Fluoroalkyl” refers to an alkyl radical, as defined above, that issubstituted by one or more fluoro radicals, as defined above, forexample, trifluoromethyl, difluoromethyl, fluoromethyl,2,2,2-trifluoroethyl, 1-fluoromethyl-2-fluoroethyl, and the like. Thealkyl part of the fluoroalkyl radical are optionally substituted asdefined above for an alkyl group.

“Haloalkoxy” refers to an alkoxy radical, as defined above, that issubstituted by one or more halo radicals, as defined above.

“Heterocycloalkyl” refers to a stable 3- to 18-membered non-aromaticring radical that comprises two to twelve carbon atoms and from one tosix heteroatoms selected from nitrogen, oxygen, and sulfur. Unlessstated otherwise specifically in the specification, the heterocycloalkylradical is a monocyclic, bicyclic, tricyclic, or tetracyclic ringsystem, which include fused, spiro, or bridged ring systems. Theheteroatoms in the heterocycloalkyl radical are optionally oxidized. Oneor more nitrogen atoms, if present, are optionally quaternized. Theheterocycloalkyl radical is partially or fully saturated. In someembodiments, the heterocycloalkyl is attached to the rest of themolecule through any atom of the ring(s). Examples of suchheterocycloalkyl radicals include, but are not limited to, dioxolanyl,thienyl[1,3]dithianyl, decahydroisoquinolyl, imidazolinyl,imidazolidinyl, isothiazolidinyl, isoxazolidinyl, morpholinyl,octahydroindolyl, octahydroisoindolyl, 2-oxopiperazinyl,2-oxopiperidinyl, 2-oxopyrrolidinyl, oxazolidinyl, piperidinyl,piperazinyl, 4-piperidonyl, pyrrolidinyl, pyrazolidinyl, quinuclidinyl,thiazolidinyl, tetrahydrofuryl, trithianyl, tetrahydropyranyl,thiomorpholinyl, thiamorpholinyl, 1-oxo-thiomorpholinyl, and1,1-dioxo-thiomorpholinyl. Unless stated otherwise specifically in thespecification, the term “heterocycloalkyl” is meant to includeheterocycloalkyl radicals as defined above that are optionallysubstituted by one or more substituents selected from alkyl, alkenyl,alkynyl, halo, fluoroalkyl, oxo, thioxo, cyano, nitro, aryl, aralkyl,aralkenyl, aralkynyl, cycloalkyl, heterocycloalkyl, heteroaryl,heteroarylalkyl, —R^(b)—OR^(a), —R^(b)—OC(O)—R^(a), —R^(b)—OC(O)—OR^(a),—R^(b)—OC(O)—N(R^(a))₂, —R^(b)—N(R^(a))₂, —R^(b)—C(O) R^(a),—R^(b)—C(O)OR^(a), —R^(b)—C(O)N(R^(a))₂, —R^(b)—O—R^(c)—C(O)N(R^(a))₂,—R^(b)—N(R^(a))C(O)OR^(a), —R^(b)—N(R^(a))C(O)R^(a),—R^(b)—N(R^(a))S(O)_(t)R^(a) (where t is 1 or 2), —R^(b)—S(O)_(t)OR^(a)(where t is 1 or 2), —R^(b)—S(O)_(t)R^(a) (where t is 1 or 2) and—R^(b)—S(O)_(t)N(R^(a))₂ (where t is 1 or 2), where each R^(a) isindependently hydrogen, alkyl, fluoroalkyl, cycloalkyl, cycloalkylalkyl,aryl, aralkyl, heterocycloalkyl, heteroaryl or heteroarylalkyl, eachR^(b) is independently a direct bond or a straight or branched alkyleneor alkenylene chain, and R^(c) is a straight or branched alkylene oralkenylene chain.

“Heteroaryl” refers to a radical derived from a 5- to 18-memberedaromatic ring radical that comprises one to seventeen carbon atoms andfrom one to six heteroatoms selected from nitrogen, oxygen, and sulfur.As used herein, the heteroaryl radical is a monocyclic, bicyclic,tricyclic, or tetracyclic ring system, wherein at least one of the ringsin the ring system is fully unsaturated, i.e., it contains a cyclic,delocalized (4n+2) π-electron system in accordance with the Hückeltheory. Heteroaryl includes fused or bridged ring systems. Theheteroatom(s) in the heteroaryl radical is optionally oxidized. One ormore nitrogen atoms, if present, are optionally quaternized. Theheteroaryl is attached to the rest of the molecule through any atom ofthe ring(s). Unless stated otherwise specifically in the specification,the term “heteroaryl” is meant to include heteroaryl radicals as definedabove that are optionally substituted by one or more substituentsselected from alkyl, alkenyl, alkynyl, halo, haloalkyl, oxo, thioxo,cyano, nitro, aryl, aralkyl, aralkenyl, aralkynyl, cycloalkyl,heterocycloalkyl, heteroaryl, heteroarylalkyl, —R^(b)—OR⁷,—R^(b)—OC(O)—R^(a), —R^(b)—OC(O)—OR^(a), —R^(b)—OC(O)—N(R^(a))₂,—R^(b)—N(R^(a))₂, —R^(b)—C(O)R^(a), —R^(b)—C(O)OR^(a),—R^(b)—C(O)N(R^(a))₂, —R^(b)—O—R^(c)—C(O)N(R^(a))₂,—R^(b)—N(R^(a))C(O)OR^(a), —R^(b)—N(R^(a))C(O)R^(a),—R^(b)—N(R^(a))S(O)_(t)R^(a) (where t is 1 or 2), —R^(b)—S(O)_(t)OR^(a)(where t is 1 or 2), —R^(b)—S(O)_(t)R^(a) (where t is 1 or 2) and—R^(b)—S(O)_(t)N(R^(a))₂ (where t is 1 or 2), where each R^(a) isindependently hydrogen, alkyl, fluoroalkyl, cycloalkyl, cycloalkylalkyl,aryl, aralkyl, heterocycloalkyl, heteroaryl, or heteroarylalkyl, eachR^(b) is independently a direct bond or a straight or branched alkyleneor alkenylene chain, and R^(c) is a straight or branched alkylene oralkenylene chain.

“N-heteroaryl” refers to a heteroaryl radical as defined abovecontaining at least one nitrogen and where the point of attachment ofthe heteroaryl radical to the rest of the molecule is through a nitrogenatom in the heteroaryl radical. An N-heteroaryl radical is optionallysubstituted as described above for heteroaryl radicals.

“C-heteroaryl” refers to a heteroaryl radical as defined above and wherethe point of attachment of the heteroaryl radical to the rest of themolecule is through a carbon atom in the heteroaryl radical. AC-heteroaryl radical is optionally substituted as described above forheteroaryl radicals.

“Heteroaryloxy” refers to radical bonded through an oxygen atom of theformula —O— heteroaryl, where heteroaryl is as defined above.

“Heteroarylalkyl” refers to a radical of the formula —R^(c)-heteroaryl,where R^(c) is an alkylene chain as defined above. If the heteroaryl isa nitrogen-containing heteroaryl, the heteroaryl is optionally attachedto the alkyl radical at the nitrogen atom. The alkylene chain of theheteroarylalkyl radical is optionally substituted as defined above foran alkylene chain. The heteroaryl part of the heteroarylalkyl radical isoptionally substituted as defined above for a heteroaryl group.

“Heteroarylalkoxy” refers to a radical bonded through an oxygen atom ofthe formula —O—R^(c)-heteroaryl, where R^(c) is an alkylene chain asdefined above. If the heteroaryl is a nitrogen-containing heteroaryl,the heteroaryl is optionally attached to the alkyl radical at thenitrogen atom. The alkylene chain of the heteroarylalkoxy radical isoptionally substituted as defined above for an alkylene chain. Theheteroaryl part of the heteroarylalkoxy radical is optionallysubstituted as defined above for a heteroaryl group.

In some embodiments, the compounds disclosed herein contain one or moreasymmetric centers and thus give rise to enantiomers, diastereomers, andother stereoisomeric forms that are defined, in terms of absolutestereochemistry, as (R)- or (S)-. Unless stated otherwise, it isintended that all stereoisomeric forms of the compounds disclosed hereinare contemplated by this disclosure. When the compounds described hereincontain alkene double bonds, and unless specified otherwise, it isintended that this disclosure includes both E and Z geometric isomers(e.g., cis or trans.) Likewise, all possible isomers, as well as theirracemic and optically pure forms, and all tautomeric forms are alsointended to be included. The term “geometric isomer” refers to E or Zgeometric isomers (e.g., cis or trans) of an alkene double bond. Theterm “positional isomer” refers to structural isomers around a centralring, such as ortho-, meta-, and para-isomers around a benzene ring.

A “tautomer” refers to a molecule wherein a proton shift from one atomof a molecule to another atom of the same molecule is possible. Incertain embodiments, the compounds presented herein exist as tautomers.In circumstances where tautomerization is possible, a chemicalequilibrium of the tautomers will exist. The exact ratio of thetautomers depends on several factors, including physical state,temperature, solvent, and pH. Some examples of tautomeric equilibriuminclude:

“Optional” or “optionally” means that a subsequently described event orcircumstance may or may not occur and that the description includesinstances when the event or circumstance occurs and instances in whichit does not. For example, “optionally substituted aryl” means that thearyl radical are or are not substituted and that the descriptionincludes both substituted aryl radicals and aryl radicals having nosubstitution.

“Pharmaceutically acceptable salt” includes both acid and base additionsalts. A pharmaceutically acceptable salt of any one of the pyrazolecompounds described herein is intended to encompass any and allpharmaceutically suitable salt forms. Preferred pharmaceuticallyacceptable salts of the compounds described herein are pharmaceuticallyacceptable acid addition salts and pharmaceutically acceptable baseaddition salts.

“Pharmaceutically acceptable acid addition salt” refers to those saltswhich retain the biological effectiveness and properties of the freebases, which are not biologically or otherwise undesirable, and whichare formed with inorganic acids such as hydrochloric acid, hydrobromicacid, sulfuric acid, nitric acid, phosphoric acid, hydroiodic acid,hydrofluoric acid, phosphorous acid, and the like. Also included aresalts that are formed with organic acids such as aliphatic mono- anddicarboxylic acids, phenyl-substituted alkanoic acids, hydroxy alkanoicacids, alkanedioic acids, aromatic acids, aliphatic and aromaticsulfonic acids, etc. and include, for example, acetic acid,trifluoroacetic acid, propionic acid, glycolic acid, pyruvic acid,oxalic acid, maleic acid, malonic acid, succinic acid, fumaric acid,tartaric acid, citric acid, benzoic acid, cinnamic acid, mandelic acid,methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid,salicylic acid, and the like. Exemplary salts thus include sulfates,pyrosulfates, bisulfates, sulfites, bisulfites, nitrates, phosphates,monohydrogenphosphates, dihydrogenphosphates, metaphosphates,pyrophosphates, chlorides, bromides, iodides, acetates,trifluoroacetates, propionates, caprylates, isobutyrates, oxalates,malonates, succinate suberates, sebacates, fumarates, maleates,mandelates, benzoates, chlorobenzoates, methylbenzoates,dinitrobenzoates, phthalates, benzenesulfonates, toluenesulfonates,phenylacetates, citrates, lactates, malates, tartrates,methanesulfonates, and the like. Also contemplated are salts of aminoacids, such as arginates, gluconates, and galacturonates (see, forexample, Berge S. M. et al., “Pharmaceutical Salts,” Journal ofPharmaceutical Science, 66:1-19 (1997)). Acid addition salts of basiccompounds are prepared by contacting the free base forms with asufficient amount of the desired acid to produce the salt.

“Pharmaceutically acceptable base addition salt” refers to those saltsthat retain the biological effectiveness and properties of the freeacids, which are not biologically or otherwise undesirable. These saltsare prepared from addition of an inorganic base or an organic base tothe free acid. In some embodiments, pharmaceutically acceptable baseaddition salts are formed with metals or amines, such as alkali andalkaline earth metals or organic amines. Salts derived from inorganicbases include, but are not limited to, sodium, potassium, lithium,ammonium, calcium, magnesium, iron, zinc, copper, manganese, aluminumsalts and the like. Salts derived from organic bases include, but arenot limited to, salts of primary, secondary, and tertiary amines,substituted amines including naturally occurring substituted amines,cyclic amines and basic ion exchange resins, for example,isopropylamine, trimethylamine, diethylamine, triethylamine,tripropylamine, ethanolamine, diethanolamine, 2-dimethylaminoethanol,2-diethylaminoethanol, dicyclohexylamine, lysine, arginine, histidine,caffeine, procaine, N,N-dibenzylethylenediamine, chloroprocaine,hydrabamine, choline, betaine, ethylenediamine, ethylenedianiline,N-methylglucamine, glucosamine, methylglucamine, theobromine, purines,piperazine, piperidine, N-ethylpiperidine, polyamine resins, and thelike. See Berge et al., supra.

For therapeutic use, salts of the compounds of the invention are thosewherein the counterion is pharmaceutically acceptable. However, salts ofacids and bases which are non-pharmaceutically acceptable may also finduse, for example, in the preparation or purification of apharmaceutically acceptable compound. All salts, whetherpharmaceutically acceptable or not are included within the ambit of thepresent invention.

The term “addition salt” or “salt”, as used herein also is meant tocomprise the solvates, which the compounds of the invention as well asthe (non-solvate) salts thereof, are able to form. Such solvates are forexample hydrates, alcoholates, e.g. methanolates, ethanolates,propanolates, and the like. Preferred are solvates that arepharmaceutically acceptable. Hence the invention also encompasses thepharmaceutically acceptable solvates of the compounds as specifiedherein.

Compounds of the present invention may exist in N-oxide form. TheN-oxide forms are meant to comprise the compounds of the inventionwherein one or several nitrogen atoms are oxidized to the so-calledN-oxide. The compounds of formula (I) may be converted to thecorresponding N-oxide forms following art-known procedures forconverting a trivalent nitrogen into its N-oxide form. Said N-oxidationreaction may generally be carried out by reacting the starting materialof formula (I) with an appropriate organic or inorganic peroxide.Appropriate inorganic peroxides comprise, for example, hydrogenperoxide, alkali metal or earth alkaline metal peroxides, e.g. sodiumperoxide, potassium peroxide; appropriate organic peroxides may compriseperoxy acids such as, for example, benzenecarbo-peroxoic acid or halosubstituted benzenecarboperoxoic acid, e.g.3-chlorobenzene-carboperoxoic acid, peroxoalkanoic acids, e.g.peroxoacetic acid, alkylhydroperoxides, e.g. tert-butyl hydroperoxide.Suitable solvents are, for example, water, lower alcohols, e.g. ethanoland the like, hydrocarbons, e.g. toluene, ketones, e.g. 2-butanone,halogenated hydrocarbons, e.g. dichloromethane, and mixtures of suchsolvents.

Compounds of the present invention may exist as quaternary amines. Theterm “quaternary amine” defines the quaternary ammonium salts which thecompounds of the invention are able to form by reaction between a basicnitrogen of a compound of the invention and an appropriate quaternizingagent, such as, for example, an optionally substituted alkyl halide,aryl halide or arylalkyl halide, e.g. methyl iodide or benzyl iodide.Other reactants with suitable leaving groups may also be used, such asalkyl trifluoromethanesulfonates, alkyl methanesulfonates, and alkylp-toluenesulfonates. A quaternary amine has a positively chargednitrogen. Pharmaceutically acceptable counterions include chloro, bromo,iodo, trifluoroacetate and acetate. The counterion of choice can beintroduced using ion exchange resins.

It will be appreciated that the compound of the present invention mayhave metal binding, chelating, complex forming properties and thereforemay exist as metal complexes or metal chelates. Such metalatedderivatives of the compounds of the invention are intended to beincluded within the scope of the present invention.

As used herein, “treatment” or “treating” or “palliating” or“ameliorating” are used interchangeably herein. These terms refer to anapproach for obtaining beneficial or desired results including, but notlimited to, therapeutic benefit and/or a prophylactic benefit. By“therapeutic benefit” is meant eradication or amelioration of theunderlying disorder being treated. Also, a therapeutic benefit isachieved with the eradication or amelioration of one or more of thephysiological symptoms associated with the underlying disorder such thatan improvement is observed in the patient, notwithstanding that thepatient is still afflicted with the underlying disorder. Forprophylactic benefit, the compositions are administered to a patient atrisk of developing a particular disease, or to a patient reporting oneor more of the physiological symptoms of a disease, even though adiagnosis of this disease has not been made.

Compounds

The compounds of Formula (I), (II), (III), (IIIa), (IIIb), or (IV)described herein are inhibitors of MAGL and/or FAAH. In someembodiments, the compounds are inhibitors of MAGL. In some embodiments,the compounds are inhibitors of FAAH. In some embodiments, the compoundsare inhibitors of MAGL and FAAH. The compounds of Formula (I), (II),(III), (IIIa), (IIIb), or (IV) described herein, and compositionscomprising these compounds, are useful for the treatment of pain or aneurological disorder.

In some embodiments is a compound of Formula (I):

wherein

-   each R¹ is independently selected from halogen, —CN, C₁₋₆alkyl,    C₂₋₆alkynyl, C₁₋₆alkyl-OR⁷, C₁₋₆haloalkyl, C₃₋₈cycloalkyl, —NR⁵R⁶,    —C(O)NR⁵R⁶, —OR⁷, —SO₂R¹², —SF₅, —SR⁸, aryl, and heteroaryl, wherein    aryl and heteroaryl are optionally substituted with one or two    groups independently selected from halogen, C₁₋₆alkyl,    C₁₋₆haloalkyl, and —C(O)NR⁸R⁹; or two adjacent R¹ form a    heterocycloalkyl ring optionally substituted with one or two R¹¹;-   R² is C₁₋₆alkyl;-   R³ is selected from halogen, —CN, C₁₋₆alkyl, C₁₋₆haloalkyl, —NR⁸R⁹,    —C(O)NR⁸R⁹, —NR⁸C(O)R⁹, and —NR⁹SO₂R⁸;-   R^(3a) is selected from halogen, C₁₋₆alkyl, and C₁₋₆haloalkyl;-   each R⁴ is independently selected from H and C₁₋₆alkyl;-   each R⁵ and R⁶ is independently selected from H, C₁₋₆alkyl, and    C₃₋₈cycloalkyl; or R⁵ and R⁶, together with the nitrogen to which    they are attached, form a heterocycloalkyl optionally substituted    with-   one or two R¹⁰;    -   each R⁷ is independently selected from H, C₁₋₆alkyl,        C₁₋₆alkyl-O—C₁₋₆alkyl, C₁₋₆haloalkyl, C₃₋₈cycloalkyl,        heterocycloalkyl, aryl, and heteroaryl, wherein        heterocycloalkyl, aryl, and heteroaryl are optionally        substituted with one or two groups independently selected from        halogen, C₁₋₆alkyl, and C₁₋₆haloalkyl;-   each R⁸ and R⁹ is independently selected from H, C₁₋₆alkyl,    C₃₋₈cycloalkyl, aryl, and heteroaryl;-   each R¹⁰ is independently selected from C₁₋₆alkyl, C₃₋₈cycloalkyl,    C₁₋₆haloalkyl, halogen, oxo, —CN, —C(O)OR⁸, —C(O)R⁸, —C(O)NR⁸R⁹,    —SO₂R⁸, —NR⁹C(O)R⁸, and —NR⁹SO₂R⁸;-   each R¹¹ is independently selected from halogen and C₁₋₆alkyl;-   each R¹² is independently selected from C₁₋₆alkyl and    C₃₋₈cycloalkyl;-   m is 0, 1, 2, 3, 4, or 5;-   n is 0, 1, 2, or 3;-   p is 0 or 1; and-   q is 0 or 1;    or a pharmaceutically acceptable salt, solvate, or stereoisomer    thereof.

In some embodiments is a compound of Formula (I), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein each R⁴ is H.In some embodiments is a compound of Formula (I), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein one R⁴ is Hand one R⁴ is C₁₋₆alkyl. In some embodiments is a compound of Formula(I), or a pharmaceutically acceptable salt, solvate, or stereoisomerthereof, wherein one R⁴ is H and one R⁴ is —CH₃. In some embodiments isa compound of Formula (I), or a pharmaceutically acceptable salt,solvate, or stereoisomer thereof, wherein one R⁴ is H and one R⁴ is—CH₂CH₃. In some embodiments is a compound of Formula (I), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein one R⁴ is H and one R⁴ is —CH₂CH₂CH₃. In some embodiments is acompound of Formula (I), or a pharmaceutically acceptable salt, solvate,or stereoisomer thereof, wherein one R⁴ is H and one R⁴ is —CH(CH₃)₂. Insome embodiments is a compound of Formula (I), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein each R⁴ isC₁₋₆alkyl. In some embodiments is a compound of Formula (I), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein each R⁴ is —CH₃.

In some embodiments is a compound of Formula (I), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein p is 0. Insome embodiments is a compound of Formula (I), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein p is 1. Insome embodiments is a compound of Formula (I), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein p is 1 and R²is —CH₃. In some embodiments is a compound of Formula (I), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein p is 1 and R² is —CH₂CH₃. In some embodiments is a compound ofFormula (I), or a pharmaceutically acceptable salt, solvate, orstereoisomer thereof, wherein p is 1 and R² is —CH₂CH₂CH₃. In someembodiments is a compound of Formula (I), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein p is 1 and R²is —CH(CH₃)₂.

In some embodiments is a compound of Formula (I), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein R³ ishalogen. In some embodiments is a compound of Formula (I), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein R³ is —CN. In some embodiments is a compound of Formula (I), ora pharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein R³ is C₁₋₆alkyl. In some embodiments is a compound of Formula(I), or a pharmaceutically acceptable salt, solvate, or stereoisomerthereof, wherein R³ is —CH₃. In some embodiments is a compound ofFormula (I), or a pharmaceutically acceptable salt, solvate, orstereoisomer thereof, wherein R³ is C₁₋₆haloalkyl. In some embodimentsis a compound of Formula (I), or a pharmaceutically acceptable salt,solvate, or stereoisomer thereof, wherein R³ is —CF₃. In someembodiments is a compound of Formula (I), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein R³ is —NR⁸R⁹.In some embodiments is a compound of Formula (I), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein R³ is —NH₂.In some embodiments is a compound of Formula (I), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein R³ is—C(O)NR⁸R⁹. In some embodiments is a compound of Formula (I), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein R³ is —C(O)NH₂. In some embodiments is a compound of Formula(I), or a pharmaceutically acceptable salt, solvate, or stereoisomerthereof, wherein R³ is —NR⁸C(O)R⁹. In some embodiments is a compound ofFormula (I), or a pharmaceutically acceptable salt, solvate, orstereoisomer thereof, wherein R³ is —NHC(O)CH₃. In some embodiments is acompound of Formula (I), or a pharmaceutically acceptable salt, solvate,or stereoisomer thereof, wherein q is 0. In some embodiments is acompound of Formula (I), or a pharmaceutically acceptable salt, solvate,or stereoisomer thereof, wherein q is 1. In some embodiments is acompound of Formula (I), or a pharmaceutically acceptable salt, solvate,or stereoisomer thereof, wherein q is 1 and R^(3a) is halogen. In someembodiments is a compound of Formula (I), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein q is 1 andR^(3a) is C₁₋₆alkyl. In some embodiments is a compound of Formula (I),or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein q is 1 and R^(3a) is C₁₋₆haloalkyl.

In some embodiments is a compound of Formula (I), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein

In some embodiments is a compound of Formula (I), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein m is 0. Insome embodiments is a compound of Formula (I), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein m is 1. Insome embodiments is a compound of Formula (I), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein m is 1 and R¹is selected from halogen, —CN, C₁₋₆alkyl, C₂₋₆alkynyl, C₁₋₆alkyl-OR⁷,C₁₋₆haloalkyl, C₃₋₈cycloalkyl, —NR⁵R⁶, —OR⁷, —SO₂R¹², —SF₅, —SR⁸, aryl,and heteroaryl. In some embodiments is a compound of Formula (I), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein m is 1 and R¹ is selected from halogen, C₁₋₆alkyl,C₁₋₆haloalkyl, C₃₋₈cycloalkyl, —NR⁵R⁶, and —OR⁷. In some embodiments isa compound of Formula (I), or a pharmaceutically acceptable salt,solvate, or stereoisomer thereof, wherein m is 1 and R¹ is selected fromhalogen, C₁₋₆alkyl, C₁₋₆haloalkyl, C₃₋₈cycloalkyl, and —OR⁷. In someembodiments is a compound of Formula (I), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein m is 1 and R¹is halogen. In some embodiments is a compound of Formula (I), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein m is 1 and R¹ is F. In some embodiments is a compound of Formula(I), or a pharmaceutically acceptable salt, solvate, or stereoisomerthereof, wherein m is 1 and R¹ is Cl. In some embodiments is a compoundof Formula (I), or a pharmaceutically acceptable salt, solvate, orstereoisomer thereof, wherein m is 1 and R¹ is —CN. In some embodimentsis a compound of Formula (I), or a pharmaceutically acceptable salt,solvate, or stereoisomer thereof, wherein m is 1 and R¹ is C₁₋₆alkyl. Insome embodiments is a compound of Formula (I), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein m is 1 and R¹is —CH₃. In some embodiments is a compound of Formula (I), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein m is 1 and R¹ is —C≡CH In some embodiments is a compound ofFormula (I), or a pharmaceutically acceptable salt, solvate, orstereoisomer thereof, wherein m is 1 and R¹ is C₁₋₆alkyl-OR⁷. In someembodiments is a compound of Formula (I), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein m is 1 and R¹is —CH₂—O—CH₃. In some embodiments is a compound of Formula (I), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein m is 1 and R¹ is C₁₋₆haloalkyl. In some embodiments is acompound of Formula (I), or a pharmaceutically acceptable salt, solvate,or stereoisomer thereof, wherein m is 1 and R¹ is —CF₃. In someembodiments is a compound of Formula (I), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein m is 1 and R¹is C₃₋₈cycloalkyl. In some embodiments is a compound of Formula (I), ora pharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein m is 1 and R¹ is —NR⁵R⁶. In some embodiments is a compound ofFormula (I), or a pharmaceutically acceptable salt, solvate, orstereoisomer thereof, wherein m is 1, R¹ is —NR⁵R⁶, and R⁵ and R⁶,together with the nitrogen to which they are attached, form aheterocycloalkyl optionally substituted with one or two R¹⁰. In someembodiments is a compound of Formula (I), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein m is 1, R¹ is—NR⁵R⁶, and R⁵ and R⁶, together with the nitrogen to which they areattached, form an unsubstituted heterocycloalkyl. In some embodiments isa compound of Formula (I), or a pharmaceutically acceptable salt,solvate, or stereoisomer thereof, wherein m is 1, R¹ is —NR⁵R⁶, and R⁵and R⁶, together with the nitrogen to which they are attached, form aheterocycloalkyl substituted with one or two R¹⁰ independently selectedfrom C₁₋₆alkyl, C₃₋₈cycloalkyl, C₁₋₆haloalkyl, halogen, oxo, —C(O)NR⁸R⁹,—SO₂R⁸, —NR⁹C(O)R⁸, and —NR⁹SO₂R⁸. In some embodiments is a compound ofFormula (I), or a pharmaceutically acceptable salt, solvate, orstereoisomer thereof, wherein m is 1, R¹ is —NR⁵R⁶, and R⁵ and R⁶,together with the nitrogen to which they are attached, form aheterocycloalkyl substituted with one or two R¹⁰ independently selectedfrom C₁₋₆alkyl, C₃₋₈cycloalkyl, and —C(O)NR⁸R⁹. In some embodiments is acompound of Formula (I), or a pharmaceutically acceptable salt, solvate,or stereoisomer thereof, wherein m is 1 and R¹ is —OR⁷. In someembodiments is a compound of Formula (I), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein m is 1, R¹ is—OR⁷, and R⁷ is selected from C₁₋₆alkyl, C₁₋₆alkyl-O—C₁₋₆alkyl,C₁₋₆haloalkyl, C₃₋₈cycloalkyl, heterocycloalkyl, aryl, and heteroaryl.In some embodiments is a compound of Formula (I), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein m is 1 and R¹is —OCH₃. In some embodiments is a compound of Formula (I), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein m is 1 and R¹ is —OCF₃. In some embodiments is a compound ofFormula (I), or a pharmaceutically acceptable salt, solvate, orstereoisomer thereof, wherein m is 1 and R¹ is —SO₂R¹². In someembodiments is a compound of Formula (I), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein m is 1 and R¹is —SF₅. In some embodiments is a compound of Formula (I), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein m is 1 and R¹ is —SR⁸. In some embodiments is a compound ofFormula (I), or a pharmaceutically acceptable salt, solvate, orstereoisomer thereof, wherein m is 1 and R¹ is aryl optionallysubstituted with one or two groups independently selected from halogen,C₁₋₆alkyl, C₁₋₆haloalkyl, and —C(O)NR⁸R⁹. In some embodiments is acompound of Formula (I), or a pharmaceutically acceptable salt, solvate,or stereoisomer thereof, wherein m is 1 and R¹ is heteroaryl optionallysubstituted with one or two groups independently selected from halogen,C₁₋₆alkyl, C₁₋₆haloalkyl, and —C(O)NR⁸R⁹. In some embodiments is acompound of Formula (I), or a pharmaceutically acceptable salt, solvate,or stereoisomer thereof, wherein m is 1 and R¹ is selected fromthiazole, pyrazine, pyrimidine, and pyridine, optionally substitutedwith one or two groups independently selected from halogen, C₁₋₆alkyl,C₁₋₆haloalkyl, and —C(O)NR⁸R⁹. In some embodiments is a compound ofFormula (I), or a pharmaceutically acceptable salt, solvate, orstereoisomer thereof, wherein m is 2. In some embodiments is a compoundof Formula (I), or a pharmaceutically acceptable salt, solvate, orstereoisomer thereof, wherein m is 2 and each R¹ is independentlyselected from halogen, —CN, C₁₋₆alkyl, C₂₋₆alkynyl, C₁₋₆alkyl-OR⁷,C₁₋₆haloalkyl, C₃₋₈cycloalkyl, —NR⁵R⁶, —OR⁷, —SO₂R¹², —SF₅, —SR⁸, aryl,and heteroaryl. In some embodiments is a compound of Formula (I), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein m is 2 and each R¹ is independently selected from halogen,C₁₋₆alkyl, C₁₋₆haloalkyl, C₃₋₈cycloalkyl, —NR⁵R⁶, and —OR⁷. In someembodiments is a compound of Formula (I), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein m is 2 andeach R¹ is independently selected from halogen, —CN, C₁₋₆alkyl,C₁₋₆haloalkyl, —NR⁵R⁶, —OR⁷, and heteroaryl. In some embodiments is acompound of Formula (I), or a pharmaceutically acceptable salt, solvate,or stereoisomer thereof, wherein m is 2 and each R¹ is independentlyselected from halogen, C₁₋₆haloalkyl, —NR⁵R⁶, —OR⁷, thiazole, pyrazine,pyrimidine, and pyridine. In some embodiments is a compound of Formula(I), or a pharmaceutically acceptable salt, solvate, or stereoisomerthereof, wherein m is 2 and each R¹ is independently selected fromhalogen, C₁₋₆alkyl, C₁₋₆haloalkyl, C₃₋₈cycloalkyl, and —OR⁷. In someembodiments is a compound of Formula (I), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein m is 2, eachR¹ is independently selected from halogen, C₁₋₆alkyl, C₁₋₆haloalkyl,C₃₋₈cycloalkyl, and —OR⁷, and each R⁷ is independently selected fromC₁₋₆alkyl, C₁₋₆alkyl-O—C₁₋₆alkyl, C₁₋₆haloalkyl, C₃₋₈cycloalkyl,heterocycloalkyl, aryl, and heteroaryl. In some embodiments is acompound of Formula (I), or a pharmaceutically acceptable salt, solvate,or stereoisomer thereof, wherein m is 2, each R¹ is independentlyselected from halogen, C₁₋₆alkyl, C₁₋₆haloalkyl, C₃₋₈cycloalkyl, and—OR⁷, and each R⁷ is independently selected from C₁₋₆alkyl,C₁₋₆haloalkyl, C₃₋₈cycloalkyl, and heterocycloalkyl. In some embodimentsis a compound of Formula (I), or a pharmaceutically acceptable salt,solvate, or stereoisomer thereof, wherein m is 3. In some embodiments isa compound of Formula (I), or a pharmaceutically acceptable salt,solvate, or stereoisomer thereof, wherein m is 3 and each R¹ isindependently selected from halogen, —CN, C₁₋₆alkyl, C₂₋₆alkynyl,C₁₋₆alkyl-OR⁷, C₁₋₆haloalkyl, C₃₋₈cycloalkyl, —NR⁵R⁶, —OR⁷, —SO₂R¹²,—SF₅, —SR⁸, aryl, and heteroaryl. In some embodiments is a compound ofFormula (I), or a pharmaceutically acceptable salt, solvate, orstereoisomer thereof, wherein m is 3 and each R¹ is independentlyselected from halogen, C₁₋₆alkyl, C₁₋₆haloalkyl, C₃₋₈cycloalkyl, —NR⁵R⁶,and —OR⁷. In some embodiments is a compound of Formula (I), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof, m is3 and each R¹ is independently selected from halogen, C₁₋₆alkyl,C₁₋₆haloalkyl, C₃₋₈cycloalkyl, and —OR⁷. In some embodiments is acompound of Formula (I), or a pharmaceutically acceptable salt, solvate,or stereoisomer thereof, wherein m is 3, each R¹ is independentlyselected from halogen, C₁₋₆alkyl, C₁₋₆haloalkyl, C₃₋₈cycloalkyl, and—OR⁷, and each R⁷ is independently selected from C₁₋₆alkyl,C₁₋₆alkyl-O—C₁₋₆alkyl, C₁₋₆haloalkyl, C₃₋₈cycloalkyl, heterocycloalkyl,aryl, and heteroaryl. In some embodiments is a compound of Formula (I),or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein m is 3, each R¹ is independently selected from halogen,C₁₋₆alkyl, C₁₋₆haloalkyl, C₃₋₈cycloalkyl, and —OR⁷, and each R⁷ isindependently selected from C₁₋₆alkyl, C₁₋₆haloalkyl, C₃₋₈cycloalkyl,and heterocycloalkyl.

In some embodiments is a compound of Formula (I), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein

In some embodiments is a compound of Formula (I), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein

In some embodiments is a compound of Formula (I), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein

In some embodiments is a compound of Formula (I), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein n is 0. Insome embodiments is a compound of Formula (I), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein n is 1. Insome embodiments is a compound of Formula (I), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein n is 1 and R¹is selected from halogen, —CN, C₁₋₆alkyl, C₂₋₆alkynyl, C₁₋₆haloalkyl,C₃₋₈cycloalkyl, —NR⁵R⁶, —OR⁷, —SO₂R¹², —SF₅, —SR⁸, aryl, and heteroaryl.In some embodiments is a compound of Formula (I), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein n is 1 and R¹is selected from halogen, C₁₋₆alkyl, C₁₋₆haloalkyl, C₃₋₈cycloalkyl,—NR⁵R⁶, and —OR⁷. In some embodiments is a compound of Formula (I), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein n is 1 and R¹ is selected from halogen, C₁₋₆alkyl,C₁₋₆haloalkyl, C₃₋₈cycloalkyl, and —OR⁷. In some embodiments is acompound of Formula (I), or a pharmaceutically acceptable salt, solvate,or stereoisomer thereof, wherein n is 1 and R¹ is halogen. In someembodiments is a compound of Formula (I), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein n is 1 and R¹is F. In some embodiments is a compound of Formula (I), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein n is 1 and R¹ is Cl. In some embodiments is a compound ofFormula (I), or a pharmaceutically acceptable salt, solvate, orstereoisomer thereof, wherein n is 1 and R¹ is —CN. In some embodimentsis a compound of Formula (I), or a pharmaceutically acceptable salt,solvate, or stereoisomer thereof, wherein n is 1 and R¹ is C₁₋₆alkyl. Insome embodiments is a compound of Formula (I), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein n is 1 and R¹is —CH₃. In some embodiments is a compound of Formula (I), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein n is 1 and R¹ is —C≡CH In some embodiments is a compound ofFormula (I), or a pharmaceutically acceptable salt, solvate, orstereoisomer thereof, wherein n is 1 and R¹ is C₁₋₆alkyl-OR⁷. In someembodiments is a compound of Formula (I), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein n is 1 and R¹is —CH₂—O—CH₃. In some embodiments is a compound of Formula (I), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein n is 1 and R¹ is C₁₋₆haloalkyl. In some embodiments is acompound of Formula (I), or a pharmaceutically acceptable salt, solvate,or stereoisomer thereof, wherein n is 1 and R¹ is —CF₃. In someembodiments is a compound of Formula (I), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein n is 1 and R¹is C₃₋₈cycloalkyl. In some embodiments is a compound of Formula (I), ora pharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein n is 1 and R¹ is —NR⁵R⁶. In some embodiments is a compound ofFormula (I), or a pharmaceutically acceptable salt, solvate, orstereoisomer thereof, wherein n is 1, R¹ is —NR⁵R⁶, and R⁵ and R⁶,together with the nitrogen to which they are attached, form aheterocycloalkyl optionally substituted with one or two R¹⁰. In someembodiments is a compound of Formula (I), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein n is 1, R¹ is—NR⁵R⁶, and R⁵ and R⁶, together with the nitrogen to which they areattached, form an unsubstituted heterocycloalkyl. In some embodiments isa compound of Formula (I), or a pharmaceutically acceptable salt,solvate, or stereoisomer thereof, wherein n is 1, R¹ is —NR⁵R⁶, and R⁵and R⁶, together with the nitrogen to which they are attached, form aheterocycloalkyl substituted with one or two R¹⁰ independently selectedfrom C₁₋₆alkyl, C₃₋₈cycloalkyl, C₁₋₆haloalkyl, halogen, oxo, —C(O)NR⁸R⁹,—SO₂R⁸, —NR⁹C(O)R⁸, and —NR⁹SO₂R⁸. In some embodiments is a compound ofFormula (I), or a pharmaceutically acceptable salt, solvate, orstereoisomer thereof, wherein n is 1, R¹ is —NR⁵R⁶, and R⁵ and R⁶,together with the nitrogen to which they are attached, form aheterocycloalkyl substituted with one or two R¹⁰ independently selectedfrom C₁₋₆alkyl, C₃₋₈cycloalkyl, and —C(O)NR⁸R⁹. In some embodiments is acompound of Formula (I), or a pharmaceutically acceptable salt, solvate,or stereoisomer thereof, wherein n is 1 and R¹ is —OR⁷. In someembodiments is a compound of Formula (I), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein n is 1, le is—OR⁷, and R⁷ is selected from C₁₋₆alkyl, C₁₋₆alkyl-O—C₁₋₆alkyl,C₁₋₆haloalkyl, C₃₋₈cycloalkyl, heterocycloalkyl, aryl, and heteroaryl.In some embodiments is a compound of Formula (I), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein n is 1 and R¹is —OCH₃. In some embodiments is a compound of Formula (I), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein n is 1 and R¹ is —OCF₃. In some embodiments is a compound ofFormula (I), or a pharmaceutically acceptable salt, solvate, orstereoisomer thereof, wherein n is 1 and R¹ is —SO₂R¹². In someembodiments is a compound of Formula (I), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein n is 1 and R¹is —SF₅. In some embodiments is a compound of Formula (I), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein n is 1 and R¹ is —SR⁸. In some embodiments is a compound ofFormula (I), or a pharmaceutically acceptable salt, solvate, orstereoisomer thereof, wherein n is 1 and R¹ is aryl optionallysubstituted with one or two groups independently selected from halogen,C₁₋₆alkyl, C₁₋₆haloalkyl, and —C(O)NR⁸R⁹. In some embodiments is acompound of Formula (I), or a pharmaceutically acceptable salt, solvate,or stereoisomer thereof, wherein n is 1 and R¹ is heteroaryl optionallysubstituted with one or two groups independently selected from halogen,C₁₋₆alkyl, C₁₋₆haloalkyl, and —C(O)NR⁸R⁹. In some embodiments is acompound of Formula (I), or a pharmaceutically acceptable salt, solvate,or stereoisomer thereof, wherein n is 1 and R¹ is selected fromthiazole, pyrazine, pyrimidine, and pyridine, optionally substitutedwith one or two groups independently selected from halogen, C₁₋₆alkyl,C₁₋₆haloalkyl, and —C(O)NR⁸R⁹. In some embodiments is a compound ofFormula (I), or a pharmaceutically acceptable salt, solvate, orstereoisomer thereof, wherein n is 2. In some embodiments is a compoundof Formula (I), or a pharmaceutically acceptable salt, solvate, orstereoisomer thereof, wherein n is 2 and each R¹ is independentlyselected from halogen, —CN, C₁₋₆alkyl, C₂₋₆alkynyl, C₁₋₆alkyl-OR⁷,C₁₋₆haloalkyl, C₃₋₈cycloalkyl, —NR⁵R⁶, —SO₂R¹², —SF₅, —SR⁸, aryl, andheteroaryl. In some embodiments is a compound of Formula (I), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein n is 2 and each R¹ is independently selected from halogen,C₁₋₆alkyl, C₁₋₆haloalkyl, C₃₋₈cycloalkyl, —NR⁵R⁶, and —OR⁷. In someembodiments is a compound of Formula (I), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein n is 2 andeach R¹ is independently selected from halogen, —CN, C₁₋₆alkyl,C₁₋₆haloalkyl, —NR⁵R⁶, —OR⁷, and heteroaryl. In some embodiments is acompound of Formula (I), or a pharmaceutically acceptable salt, solvate,or stereoisomer thereof, wherein n is 2 and each R¹ is independentlyselected from halogen, C₁₋₆haloalkyl, —NR⁵R⁶, thiazole, pyrazine,pyrimidine, and pyridine. In some embodiments is a compound of Formula(I), or a pharmaceutically acceptable salt, solvate, or stereoisomerthereof, wherein n is 2 and each R¹ is independently selected fromhalogen, C₁₋₆alkyl, C₁₋₆haloalkyl, C₃₋₈cycloalkyl, and —OR⁷. In someembodiments is a compound of Formula (I), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein n is 2, eachR¹ is independently selected from halogen, C₁₋₆alkyl, C₁₋₆haloalkyl,C₃₋₈cycloalkyl, and —OR⁷, and each R⁷ is independently selected fromC₁₋₆alkyl, C₁₋₆alkyl-O—C₁₋₆alkyl, C₁₋₆haloalkyl, C₃₋₈cycloalkyl,heterocycloalkyl, aryl, and heteroaryl. In some embodiments is acompound of Formula (I), or a pharmaceutically acceptable salt, solvate,or stereoisomer thereof, wherein n is 2, each R¹ is independentlyselected from halogen, C₁₋₆alkyl, C₁₋₆haloalkyl, C₃₋₈cycloalkyl, and—OR⁷, and each R⁷ is independently selected from C₁₋₆alkyl,C₁₋₆haloalkyl, C₃₋₈cycloalkyl, and heterocycloalkyl. In some embodimentsis a compound of Formula (I), or a pharmaceutically acceptable salt,solvate, or stereoisomer thereof, wherein n is 3.

In some embodiments is a compound of Formula (II):

wherein:

-   each R¹ is independently selected from halogen, —CN, C₁₋₆alkyl,    C₂₋₆alkynyl, C₁₋₆alkyl-OR⁷, C₁₋₆haloalkyl, C₃₋₈cycloalkyl, —NR⁵R⁶,    —C(O)NR⁵R⁶, —OR⁷, —SO₂R¹², —SF₅, —SR⁸, aryl, and heteroaryl, wherein    aryl and heteroaryl are optionally substituted with one or two    groups independently selected from halogen, C₁₋₆alkyl,    C₁₋₆haloalkyl, and —C(O)NR⁸R⁹; or two adjacent R¹ form a    heterocycloalkyl ring optionally substituted with one or two R¹¹;-   R² is C₁₋₆alkyl;-   R³ is selected from halogen, —CN, C₁₋₆alkyl, C₁₋₆haloalkyl, —NR⁸R⁹,    —C(O)NR⁸R⁹, —NR⁸C(O)R⁹, and —NR⁹SO₂R⁸;-   R^(3a) is selected from halogen, C₁₋₆alkyl, and C₁₋₆haloalkyl;-   each R⁵ and R⁶ is independently selected from H, C₁₋₆alkyl, and    C₃₋₈cycloalkyl; or R⁵ and R⁶, together with the nitrogen to which    they are attached, form a heterocycloalkyl optionally substituted    with one or two R¹⁰;-   each R⁷ is independently selected from H, C₁₋₆alkyl,    C₁₋₆alkyl-O—C₁₋₆alkyl, C₁₋₆haloalkyl, C₃₋₈cycloalkyl,    heterocycloalkyl, aryl, and heteroaryl, wherein heterocycloalkyl,    aryl, and heteroaryl are optionally substituted with one or two    groups independently selected from halogen, C₁₋₆alkyl, and    C₁₋₆haloalkyl;-   each R⁸ and R⁹ is independently selected from H, C₁₋₆alkyl,    C₃₋₈cycloalkyl, aryl, and heteroaryl;-   each R¹⁰ is independently selected from C₁₋₆alkyl, C₃₋₈cycloalkyl,    C₁₋₆haloalkyl, halogen, oxo, —CN, —C(O)OR⁸, —C(O)R⁸, —C(O)NR⁸R⁹,    —SO₂R⁸, —NR⁹C(O)R⁸, and —NR⁹SO₂R⁸;-   each R¹¹ is independently selected from halogen and C₁₋₆alkyl;-   each R¹² is independently selected from C₁₋₆alkyl and    C₃₋₈cycloalkyl;-   m is 0, 1, 2, 3, 4, or 5;-   n is 0, 1, 2, or 3;-   p is 0 or 1; and-   q is 0 or 1;    or a pharmaceutically acceptable salt, solvate, or stereoisomer    thereof.

In some embodiments is a compound of Formula (II), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein p is 0. Insome embodiments is a compound of Formula (II), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein p is 1. Insome embodiments is a compound of Formula (II), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein p is 1 and R²is —CH₃. In some embodiments is a compound of Formula (II), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein p is 1 and R² is —CH₂CH₃. In some embodiments is a compound ofFormula (II), or a pharmaceutically acceptable salt, solvate, orstereoisomer thereof, wherein p is 1 and R² is —CH₂CH₂CH₃. In someembodiments is a compound of Formula (II), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein p is 1 and R²is —CH(CH₃)₂.

In some embodiments is a compound of Formula (II), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein R³ ishalogen. In some embodiments is a compound of Formula (II), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein R³ is —CN. In some embodiments is a compound of Formula (II), ora pharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein R³ is C₁₋₆alkyl. In some embodiments is a compound of Formula(II), or a pharmaceutically acceptable salt, solvate, or stereoisomerthereof, wherein R³ is —CH₃. In some embodiments is a compound ofFormula (II), or a pharmaceutically acceptable salt, solvate, orstereoisomer thereof, wherein R³ is C₁₋₆haloalkyl. In some embodimentsis a compound of Formula (II), or a pharmaceutically acceptable salt,solvate, or stereoisomer thereof, wherein R³ is —CF₃. In someembodiments is a compound of Formula (II), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein R³ is —NR⁸R⁹.In some embodiments is a compound of Formula (II), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein R³ is —NH₂.In some embodiments is a compound of Formula (II), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein R³ is—C(O)NR⁸R⁹. In some embodiments is a compound of Formula (II), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein R³ is —C(O)NH₂. In some embodiments is a compound of Formula(II), or a pharmaceutically acceptable salt, solvate, or stereoisomerthereof, wherein R³ is —NR⁸C(O)R⁹. In some embodiments is a compound ofFormula (II), or a pharmaceutically acceptable salt, solvate, orstereoisomer thereof, wherein R³ is —NHC(O)CH₃. In some embodiments is acompound of Formula (II), or a pharmaceutically acceptable salt,solvate, or stereoisomer thereof, wherein q is 0. In some embodiments isa compound of Formula (II), or a pharmaceutically acceptable salt,solvate, or stereoisomer thereof, wherein q is 1. In some embodiments isa compound of Formula (II), or a pharmaceutically acceptable salt,solvate, or stereoisomer thereof, wherein q is 1 and R^(3a) is halogen.In some embodiments is a compound of Formula (II), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein q is 1 andR^(3a) is C₁₋₆alkyl. In some embodiments is a compound of Formula (II),or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein q is 1 and R^(3a) is C₁₋₆haloalkyl.

In some embodiments is a compound of Formula (II), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein

In some embodiments is a compound of Formula (II), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein m is 0. Insome embodiments is a compound of Formula (II), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein m is 1. Insome embodiments is a compound of Formula (II), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein m is 1 and R¹is selected from halogen, —CN, C₁₋₆alkyl, C₂₋₆alkynyl, C₁₋₆alkyl-OR⁷,C₁₋₆haloalkyl, C₃₋₈cycloalkyl, —NR⁵R⁶, —OR⁷, —SO₂R¹², —SF₅, —SR⁸, aryl,and heteroaryl. In some embodiments is a compound of Formula (II), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein m is 1 and R¹ is selected from halogen, C₁₋₆alkyl,C₁₋₆haloalkyl, C₃₋₈cycloalkyl, —NR⁵R⁶, and —OR⁷. In some embodiments isa compound of Formula (II), or a pharmaceutically acceptable salt,solvate, or stereoisomer thereof, wherein m is 1 and R¹ is selected fromhalogen, C₁₋₆alkyl, C₁₋₆haloalkyl, C₃₋₈cycloalkyl, and —OR⁷. In someembodiments is a compound of Formula (II), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein m is 1 and R¹is halogen. In some embodiments is a compound of Formula (II), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein m is 1 and R¹ is F. In some embodiments is a compound of Formula(II), or a pharmaceutically acceptable salt, solvate, or stereoisomerthereof, wherein m is 1 and R¹ is Cl. In some embodiments is a compoundof Formula (II), or a pharmaceutically acceptable salt, solvate, orstereoisomer thereof, wherein m is 1 and R¹ is —CN. In some embodimentsis a compound of Formula (II), or a pharmaceutically acceptable salt,solvate, or stereoisomer thereof, wherein m is 1 and R¹ is C₁₋₆alkyl. Insome embodiments is a compound of Formula (II), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein m is 1 and R¹is —CH₃. In some embodiments is a compound of Formula (II), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein m is 1 and R¹ is —C≡CH In some embodiments is a compound ofFormula (II), or a pharmaceutically acceptable salt, solvate, orstereoisomer thereof, wherein m is 1 and R¹ is C₁₋₆alkyl-OR⁷. In someembodiments is a compound of Formula (II), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein m is 1 and R¹is —CH₂—O—CH₃. In some embodiments is a compound of Formula (II), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein m is 1 and R¹ is C₁₋₆haloalkyl. In some embodiments is acompound of Formula (II), or a pharmaceutically acceptable salt,solvate, or stereoisomer thereof, wherein m is 1 and R¹ is —CF₃. In someembodiments is a compound of Formula (II), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein m is 1 and R¹is C₃₋₈cycloalkyl. In some embodiments is a compound of Formula (II), ora pharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein m is 1 and R¹ is —NR⁵R⁶. In some embodiments is a compound ofFormula (II), or a pharmaceutically acceptable salt, solvate, orstereoisomer thereof, wherein m is 1, R¹ is —NR⁵R⁶, and R⁵ and R⁶,together with the nitrogen to which they are attached, form aheterocycloalkyl optionally substituted with one or two R¹⁰. In someembodiments is a compound of Formula (II), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein m is 1, R¹ is—NR⁵R⁶, and R⁵ and R⁶, together with the nitrogen to which they areattached, form an unsubstituted heterocycloalkyl. In some embodiments isa compound of Formula (II), or a pharmaceutically acceptable salt,solvate, or stereoisomer thereof, wherein m is 1, R¹ is —NR⁵R⁶, and R⁵and R⁶, together with the nitrogen to which they are attached, form aheterocycloalkyl substituted with one or two R¹⁰ independently selectedfrom C₁₋₆alkyl, C₃₋₈cycloalkyl, C₁₋₆haloalkyl, halogen, oxo, —C(O)NR⁸R⁹,—SO₂R⁸, —NR⁹C(O)R⁸, and —NR⁹SO₂R⁸. In some embodiments is a compound ofFormula (II), or a pharmaceutically acceptable salt, solvate, orstereoisomer thereof, wherein m is 1, R¹ is —NR⁵R⁶, and R⁵ and R⁶,together with the nitrogen to which they are attached, form aheterocycloalkyl substituted with one or two R¹⁰ independently selectedfrom C₁₋₆alkyl, C₃₋₈cycloalkyl, and —C(O)NR⁸R⁹. In some embodiments is acompound of Formula (II), or a pharmaceutically acceptable salt,solvate, or stereoisomer thereof, wherein m is 1 and R¹ is —OR⁷. In someembodiments is a compound of Formula (II), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein m is 1, R¹ is—OR⁷, and R⁷ is selected from C₁₋₆alkyl, C₁₋₆alkyl-O—C₁₋₆alkyl,C₁₋₆haloalkyl, C₃₋₈cycloalkyl, heterocycloalkyl, aryl, and heteroaryl.In some embodiments is a compound of Formula (II), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein m is 1 and R¹is —OCH₃. In some embodiments is a compound of Formula (II), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein m is 1 and R¹ is —OCF₃. In some embodiments is a compound ofFormula (II), or a pharmaceutically acceptable salt, solvate, orstereoisomer thereof, wherein m is 1 and R¹ is —SO₂R¹². In someembodiments is a compound of Formula (II), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein m is 1 and R¹is —SF₅. In some embodiments is a compound of Formula (II), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein m is 1 and R¹ is —SR⁸. In some embodiments is a compound ofFormula (II), or a pharmaceutically acceptable salt, solvate, orstereoisomer thereof, wherein m is 1 and R¹ is aryl optionallysubstituted with one or two groups independently selected from halogen,C₁₋₆alkyl, C₁₋₆haloalkyl, and —C(O)NR⁸R⁹. In some embodiments is acompound of Formula (II), or a pharmaceutically acceptable salt,solvate, or stereoisomer thereof, wherein m is 1 and R¹ is heteroaryloptionally substituted with one or two groups independently selectedfrom halogen, C₁₋₆alkyl, C₁₋₆haloalkyl, and —C(O)NR⁸R⁹. In someembodiments is a compound of Formula (II), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein m is 1 and R¹is selected from thiazole, pyrazine, pyrimidine, and pyridine,optionally substituted with one or two groups independently selectedfrom halogen, C₁₋₆alkyl, C₁₋₆haloalkyl, and —C(O)NR⁸R⁹. In someembodiments is a compound of Formula (II), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein m is 2. Insome embodiments is a compound of Formula (II), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein m is 2 andeach R¹ is independently selected from halogen, —CN, C₁₋₆alkyl,C₂₋₆alkynyl, C₁₋₆alkyl-OR⁷, C₁₋₆haloalkyl, C₃₋₈cycloalkyl, —NR⁵R⁶, —OR⁷,—SO₂R¹², —SF₅, —S1e, aryl, and heteroaryl. In some embodiments is acompound of Formula (II), or a pharmaceutically acceptable salt,solvate, or stereoisomer thereof, wherein m is 2 and each R¹ isindependently selected from halogen, C₁₋₆alkyl, C₁₋₆haloalkyl,C₃₋₈cycloalkyl, —NR⁵R⁶, and —OR⁷. In some embodiments is a compound ofFormula (II), or a pharmaceutically acceptable salt, solvate, orstereoisomer thereof, wherein m is 2 and each R¹ is independentlyselected from halogen, —CN, C₁₋₆alkyl, C₁₋₆haloalkyl, —NR⁵R⁶, —OR⁷, andheteroaryl. In some embodiments is a compound of Formula (II), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein m is 2 and each R¹ is independently selected from halogen,C₁₋₆haloalkyl, —NR⁵R⁶, —OR⁷, thiazole, pyrazine, pyrimidine, andpyridine. In some embodiments is a compound of Formula (II), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein m is 2 and each R¹ is independently selected from halogen,C₁₋₆alkyl, C₁₋₆haloalkyl, C₃₋₈cycloalkyl, and —OR⁷. In some embodimentsis a compound of Formula (II), or a pharmaceutically acceptable salt,solvate, or stereoisomer thereof, wherein m is 2, each R¹ isindependently selected from halogen, C₁₋₆alkyl, C₁₋₆haloalkyl,C₃₋₈cycloalkyl, and —OR⁷, and each R⁷ is independently selected fromC₁₋₆alkyl, C₁₋₆alkyl-O—C₁₋₆alkyl, C₁₋₆haloalkyl, C₃₋₈cycloalkyl,heterocycloalkyl, aryl, and heteroaryl. In some embodiments is acompound of Formula (II), or a pharmaceutically acceptable salt,solvate, or stereoisomer thereof, wherein m is 2, each R¹ isindependently selected from halogen, C₁₋₆alkyl, C₁₋₆haloalkyl,C₃₋₈cycloalkyl, and —OR⁷, and each R⁷ is independently selected fromC₁₋₆alkyl, C₁₋₆haloalkyl, C₃₋₈cycloalkyl, and heterocycloalkyl. In someembodiments is a compound of Formula (II), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein m is 3. Insome embodiments is a compound of Formula (II), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein m is 3 andeach R¹ is independently selected from halogen, —CN, C₁₋₆alkyl,C₂₋₆alkynyl, C₁₋₆alkyl-OR⁷, C₁₋₆haloalkyl, C₃₋₈cycloalkyl, —NR⁵R⁶, —OR⁷,—SO₂R¹², —SF₅, —SR⁸, aryl, and heteroaryl. In some embodiments is acompound of Formula (II), or a pharmaceutically acceptable salt,solvate, or stereoisomer thereof, wherein m is 3 and each R¹ isindependently selected from halogen, C₁₋₆alkyl, C₁₋₆haloalkyl,C₃₋₈cycloalkyl, —NR⁵R⁶, and —OR⁷. In some embodiments is a compound ofFormula (II), or a pharmaceutically acceptable salt, solvate, orstereoisomer thereof, m is 3 and each R¹ is independently selected fromhalogen, C₁₋₆alkyl, C₁₋₆haloalkyl, C₃₋₈cycloalkyl, and —OR⁷. In someembodiments is a compound of Formula (II), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein m is 3, eachR¹ is independently selected from halogen, C₁₋₆alkyl, C₁₋₆haloalkyl,C₃₋₈cycloalkyl, and —OR⁷, and each R⁷ is independently selected fromC₁₋₆alkyl, C₁₋₆alkyl-O—C₁₋₆alkyl, C₁₋₆haloalkyl, C₃₋₈cycloalkyl,heterocycloalkyl, aryl, and heteroaryl. In some embodiments is acompound of Formula (II), or a pharmaceutically acceptable salt,solvate, or stereoisomer thereof, wherein m is 3, each R¹ isindependently selected from halogen, C₁₋₆alkyl, C₁₋₆haloalkyl,C₃₋₈cycloalkyl, and —OR⁷, and each R⁷ is independently selected fromC₁₋₆alkyl, C₁₋₆haloalkyl, C₃₋₈cycloalkyl, and heterocycloalkyl.

In some embodiments is a compound of Formula (II), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein

In some embodiments is a compound of Formula (II), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein

In some embodiments is a compound of Formula (II), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein

In some embodiments is a compound of Formula (II), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein n is 0. Insome embodiments is a compound of Formula (II), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein n is 1. Insome embodiments is a compound of Formula (II), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein n is 1 and R¹is selected from halogen, —CN, C₁₋₆alkyl, C₂₋₆alkynyl, C₁₋₆alkyl-OR⁷,C₁₋₆haloalkyl, C₃₋₈cycloalkyl, —NR⁵R⁶, —OR⁷, —SO₂R¹², —SF₅, —SR⁸, aryl,and heteroaryl. In some embodiments is a compound of Formula (II), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein n is 1 and R¹ is selected from halogen, C₁₋₆alkyl,C₁₋₆haloalkyl, C₃₋₈cycloalkyl, —NR⁵R⁶, and —OR⁷. In some embodiments isa compound of Formula (II), or a pharmaceutically acceptable salt,solvate, or stereoisomer thereof, wherein n is 1 and R¹ is selected fromhalogen, C₁₋₆alkyl, C₁₋₆haloalkyl, C₃₋₈cycloalkyl, and —OR⁷. In someembodiments is a compound of Formula (II), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein n is 1 and R¹is halogen. In some embodiments is a compound of Formula (II), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein n is 1 and R¹ is F. In some embodiments is a compound of Formula(II), or a pharmaceutically acceptable salt, solvate, or stereoisomerthereof, wherein n is 1 and R¹ is Cl. In some embodiments is a compoundof Formula (II), or a pharmaceutically acceptable salt, solvate, orstereoisomer thereof, wherein n is 1 and R¹ is —CN. In some embodimentsis a compound of Formula (II), or a pharmaceutically acceptable salt,solvate, or stereoisomer thereof, wherein n is 1 and R¹ is C₁₋₆alkyl. Insome embodiments is a compound of Formula (II), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein n is 1 and R¹is —CH₃. In some embodiments is a compound of Formula (II), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein n is 1 and R¹ is —C≡CH In some embodiments is a compound ofFormula (II), or a pharmaceutically acceptable salt, solvate, orstereoisomer thereof, wherein n is 1 and R¹ is C₁₋₆alkyl-OR⁷. In someembodiments is a compound of Formula (II), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein n is 1 and R¹is —CH₂—O—CH₃. In some embodiments is a compound of Formula (II), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein n is 1 and R¹ is C₁₋₆haloalkyl. In some embodiments is acompound of Formula (II), or a pharmaceutically acceptable salt,solvate, or stereoisomer thereof, wherein n is 1 and R¹ is —CF₃. In someembodiments is a compound of Formula (II), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein n is 1 and R¹is C₃₋₈cycloalkyl. In some embodiments is a compound of Formula (II), ora pharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein n is 1 and R¹ is —NR⁵R⁶. In some embodiments is a compound ofFormula (II), or a pharmaceutically acceptable salt, solvate, orstereoisomer thereof, wherein n is 1, R¹ is —NR⁵R⁶, and R⁵ and R⁶,together with the nitrogen to which they are attached, form aheterocycloalkyl optionally substituted with one or two R¹⁰. In someembodiments is a compound of Formula (II), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein n is 1, R¹ is—NR⁵R⁶, and R⁵ and R⁶, together with the nitrogen to which they areattached, form an unsubstituted heterocycloalkyl. In some embodiments isa compound of Formula (II), or a pharmaceutically acceptable salt,solvate, or stereoisomer thereof, wherein n is 1, R¹ is —NR⁵R⁶, and R⁵and R⁶, together with the nitrogen to which they are attached, form aheterocycloalkyl substituted with one or two R¹⁰ independently selectedfrom C₁₋₆alkyl, C₃₋₈cycloalkyl, C₁₋₆haloalkyl, halogen, oxo, —C(O)NR⁸R⁹,—SO₂R⁸, —NR⁹C(O)R⁸, and —NR⁹SO₂R⁸. In some embodiments is a compound ofFormula (II), or a pharmaceutically acceptable salt, solvate, orstereoisomer thereof, wherein n is 1, R¹ is —NR⁵R⁶, and R⁵ and R⁶,together with the nitrogen to which they are attached, form aheterocycloalkyl substituted with one or two R¹⁰ independently selectedfrom C₁₋₆alkyl, C₃₋₈cycloalkyl, and —C(O)NR⁸R⁹. In some embodiments is acompound of Formula (II), or a pharmaceutically acceptable salt,solvate, or stereoisomer thereof, wherein n is 1 and R¹ is —OR⁷. In someembodiments is a compound of Formula (II), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein n is 1, le is—OR⁷, and R⁷ is selected from C₁₋₆alkyl, C₁₋₆alkyl-O—C₁₋₆alkyl,C₁₋₆haloalkyl, C₃₋₈cycloalkyl, heterocycloalkyl, aryl, and heteroaryl.In some embodiments is a compound of Formula (II), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein n is 1 and R¹is —OCH₃. In some embodiments is a compound of Formula (II), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein n is 1 and R¹ is —OCF₃. In some embodiments is a compound ofFormula (II), or a pharmaceutically acceptable salt, solvate, orstereoisomer thereof, wherein n is 1 and R¹ is —SO₂R¹². In someembodiments is a compound of Formula (II), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein n is 1 and R¹is —SF₅. In some embodiments is a compound of Formula (II), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein n is 1 and R¹ is —SR⁸. In some embodiments is a compound ofFormula (II), or a pharmaceutically acceptable salt, solvate, orstereoisomer thereof, wherein n is 1 and R¹ is aryl optionallysubstituted with one or two groups independently selected from halogen,C₁₋₆alkyl, C₁₋₆haloalkyl, and —C(O)NR⁸R⁹. In some embodiments is acompound of Formula (II), or a pharmaceutically acceptable salt,solvate, or stereoisomer thereof, wherein n is 1 and R¹ is heteroaryloptionally substituted with one or two groups independently selectedfrom halogen, C₁₋₆alkyl, C₁₋₆haloalkyl, and —C(O)NR⁸R⁹. In someembodiments is a compound of Formula (II), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein n is 1 and R¹is selected from thiazole, pyrazine, pyrimidine, and pyridine,optionally substituted with one or two groups independently selectedfrom halogen, C₁₋₆alkyl, C₁₋₆haloalkyl, and —C(O)NR⁸R⁹. In someembodiments is a compound of Formula (II), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein n is 2. Insome embodiments is a compound of Formula (II), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein n is 2 andeach R¹ is independently selected from halogen, —CN, C₁₋₆alkyl,C₂₋₆alkynyl, C₁₋₆alkyl-OR⁷, C₁₋₆haloalkyl, C₃₋₈cycloalkyl, —NR⁵R⁶, —OR⁷,—SO₂R¹², —SF₅, —SR⁸, aryl, and heteroaryl. In some embodiments is acompound of Formula (II), or a pharmaceutically acceptable salt,solvate, or stereoisomer thereof, wherein n is 2 and each R¹ isindependently selected from halogen, C₁₋₆alkyl, C₁₋₆haloalkyl,C₃₋₈cycloalkyl, —NR⁵R⁶, and —OR⁷. In some embodiments is a compound ofFormula (II), or a pharmaceutically acceptable salt, solvate, orstereoisomer thereof, wherein n is 2 and each R¹ is independentlyselected from halogen, —CN, C₁₋₆alkyl, C₁₋₆haloalkyl, —NR⁵R⁶, —OR⁷, andheteroaryl. In some embodiments is a compound of Formula (II), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein n is 2 and each R¹ is independently selected from halogen,C₁₋₆haloalkyl, —NR⁵R⁶, —OR⁷, thiazole, pyrazine, pyrimidine, andpyridine. In some embodiments is a compound of Formula (II), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein n is 2 and each R¹ is independently selected from halogen,C₁₋₆alkyl, C₁₋₆haloalkyl, C₃₋₈cycloalkyl, and —OR⁷. In some embodimentsis a compound of Formula (II), or a pharmaceutically acceptable salt,solvate, or stereoisomer thereof, wherein n is 2, each R¹ isindependently selected from halogen, C₁₋₆alkyl, C₁₋₆haloalkyl,C₃₋₈cycloalkyl, and —OR⁷, and each R⁷ is independently selected fromC₁₋₆alkyl, C₁₋₆alkyl-O—C₁₋₆alkyl, C₁₋₆haloalkyl, C₃₋₈cycloalkyl,heterocycloalkyl, aryl, and heteroaryl. In some embodiments is acompound of Formula (II), or a pharmaceutically acceptable salt,solvate, or stereoisomer thereof, wherein n is 2, each R¹ isindependently selected from halogen, C₁₋₆alkyl, C₁₋₆haloalkyl,C₃₋₈cycloalkyl, and —OR⁷, and each R⁷ is independently selected fromC₁₋₆alkyl, C₁₋₆haloalkyl, C₃₋₈cycloalkyl, and heterocycloalkyl. In someembodiments is a compound of Formula (II), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein n is 3.

In some embodiments is a compound of Formula (III):

wherein:

-   each R¹ is independently selected from halogen, —CN, C₁₋₆alkyl,    C₂₋₆alkynyl, C₁₋₆alkyl-OR⁷, C₁₋₆haloalkyl, C₃₋₈cycloalkyl, —NR⁵R⁶,    —C(O)NR⁵R⁶, —OR⁷, —SO₂R¹², —SF₅, —SR⁸, aryl, and heteroaryl, wherein    aryl and heteroaryl are optionally substituted with one or two    groups independently selected from halogen, C₁₋₆alkyl,    C₁₋₆haloalkyl, and —C(O)NR⁸R⁹; or two adjacent R¹ form a    heterocycloalkyl ring optionally substituted with one or two R¹¹;-   R³ is selected from halogen, —CN, C₁₋₆alkyl, C₁₋₆haloalkyl, —NR⁸R⁹,    —C(O)NR⁸R⁹, —NR⁸C(O)R⁹, and —NR⁹SO₂R⁸;-   R^(3a) is selected from halogen, C₁₋₆alkyl, and C₁₋₆haloalkyl;-   each R⁵ and R⁶ is independently selected from H, C₁₋₆alkyl, and    C₃₋₈cycloalkyl; or R⁵ and R⁶, together with the nitrogen to which    they are attached, form a heterocycloalkyl optionally substituted    with one or two R¹⁰;-   each R⁷ is independently selected from H, C₁₋₆alkyl,    C₁₋₆alkyl-O—C₁₋₆alkyl, C₁₋₆haloalkyl, C₃₋₈cycloalkyl,    heterocycloalkyl, aryl, and heteroaryl, wherein heterocycloalkyl,    aryl, and heteroaryl are optionally substituted with one or two    groups independently selected from halogen, C₁₋₆alkyl, and    C₁₋₆haloalkyl;-   each R⁸ and R⁹ is independently selected from H, C₁₋₆alkyl,    C₃₋₈cycloalkyl, aryl, and heteroaryl;-   each R¹⁰ is independently selected from C₁₋₆alkyl, C₃₋₈cycloalkyl,    C₁₋₆haloalkyl, halogen, oxo, —CN, —C(O)OR⁸, —C(O)R⁸, —C(O)NR⁸R⁹,    —SO₂R⁸, —NR⁹C(O)R⁸, and —NR⁹SO₂R⁸;-   each R¹¹ is independently selected from halogen and C₁₋₆alkyl;-   each R¹² is independently selected from C₁₋₆alkyl and    C₃₋₈cycloalkyl;-   m is 0, 1, 2, 3, 4, or 5;-   q is 0 or 1;-   w is 1 or 2;-   x is 0 or 1;-   y is 0 or 1; and-   z is 0 or 1;    wherein when y and z are 0, then x is 1 and w is 2;    when y and z are 1, then w is 1; and    when y is 1 and z is 0, or y is 0 and z is 1, then x is 1;    or a pharmaceutically acceptable salt, solvate, or stereoisomer    thereof.

In some embodiments is a compound of Formula (III), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein y is 1, z is 1, w is 1, and x is 0. In some embodiments is acompound of Formula (III), or a pharmaceutically acceptable salt,solvate, or stereoisomer thereof, wherein y is 1, z is 1, w is 1, and xis 1. In some embodiments is a compound of Formula (III), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein y is 1, z is 0, w is 1, and x is 1. In some embodiments is acompound of Formula (III), or a pharmaceutically acceptable salt,solvate, or stereoisomer thereof, wherein y is 1, z is 0, w is 2, and xis 1. In some embodiments is a compound of Formula (III), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein y is 0, z is 0, w is 2, and x is 1.

In some embodiments is a compound of Formula (III), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein R³ is halogen. In some embodiments is a compound of Formula(III), or a pharmaceutically acceptable salt, solvate, or stereoisomerthereof, wherein R³ is —CN. In some embodiments is a compound of Formula(III), or a pharmaceutically acceptable salt, solvate, or stereoisomerthereof, wherein R³ is C₁₋₆alkyl. In some embodiments is a compound ofFormula (III), or a pharmaceutically acceptable salt, solvate, orstereoisomer thereof, wherein R³ is —CH₃. In some embodiments is acompound of Formula (III), or a pharmaceutically acceptable salt,solvate, or stereoisomer thereof, wherein R³ is C₁₋₆haloalkyl. In someembodiments is a compound of Formula (III), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein R³ is —CF₃.In some embodiments is a compound of Formula (III), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein R³ is —NR⁸R⁹. In some embodiments is a compound of Formula(III), or a pharmaceutically acceptable salt, solvate, or stereoisomerthereof, wherein R³ is —NH₂. In some embodiments is a compound ofFormula (III), or a pharmaceutically acceptable salt, solvate, orstereoisomer thereof, wherein R³ is —C(O)NR⁸R⁹. In some embodiments is acompound of Formula (III), or a pharmaceutically acceptable salt,solvate, or stereoisomer thereof, wherein R³ is —C(O)NH₂. In someembodiments is a compound of Formula (III), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein R³ is—NR⁸C(O)R⁹. In some embodiments is a compound of Formula (III), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein R³ is —NHC(O)CH₃. In some embodiments is a compound of Formula(III), or a pharmaceutically acceptable salt, solvate, or stereoisomerthereof, wherein q is 0. In some embodiments is a compound of Formula(III), or a pharmaceutically acceptable salt, solvate, or stereoisomerthereof, wherein q is 1. In some embodiments is a compound of Formula(III), or a pharmaceutically acceptable salt, solvate, or stereoisomerthereof, wherein q is 1 and R^(3a) is halogen. In some embodiments is acompound of Formula (III), or a pharmaceutically acceptable salt,solvate, or stereoisomer thereof, wherein q is 1 and R^(3a) isC₁₋₆alkyl. In some embodiments is a compound of Formula (III), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein q is 1 and R^(3a) is C₁₋₆haloalkyl.

In some embodiments is a compound of Formula (III), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein m is 0. In some embodiments is a compound of Formula (III), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein m is 1. In some embodiments is a compound of Formula (III), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein m is 1 and R¹ is selected from halogen, —CN, C₁₋₆alkyl,C₂₋₆alkynyl, C₁₋₆alkyl-OR⁷, C₁₋₆haloalkyl, C₃₋₈cycloalkyl, —NR⁵R⁶, —OR⁷,—SO₂R¹², —SF₅, —SR⁸, aryl, and heteroaryl. In some embodiments is acompound of Formula (III), or a pharmaceutically acceptable salt,solvate, or stereoisomer thereof, wherein m is 1 and R¹ is selected fromhalogen, C₁₋₆alkyl, C₁₋₆haloalkyl, C₃₋₈cycloalkyl, —NR⁵R⁶, and —OR⁷. Insome embodiments is a compound of Formula (III), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein m is 1 and R¹is selected from halogen, C₁₋₆alkyl, C₁₋₆haloalkyl, C₃₋₈cycloalkyl, and—OR⁷. In some embodiments is a compound of Formula (III), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein m is 1 and R¹ is halogen. In some embodiments is a compound ofFormula (III), or a pharmaceutically acceptable salt, solvate, orstereoisomer thereof, wherein m is 1 and R¹ is F. In some embodiments isa compound of Formula (III), or a pharmaceutically acceptable salt,solvate, or stereoisomer thereof, wherein m is 1 and R¹ is Cl. In someembodiments is a compound of Formula (III), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein m is 1 and R¹is —CN. In some embodiments is a compound of Formula (III), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein m is 1 and R¹ is C₁₋₆alkyl. In some embodiments is a compound ofFormula (III), or a pharmaceutically acceptable salt, solvate, orstereoisomer thereof, wherein m is 1 and R¹ is —CH₃. In some embodimentsis a compound of Formula (III), or a pharmaceutically acceptable salt,solvate, or stereoisomer thereof, wherein m is 1 and R¹ is —C≡CH In someembodiments is a compound of Formula (III), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein m is 1 and R¹is C₁₋₆alkyl-OR⁷. In some embodiments is a compound of Formula (III), ora pharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein m is 1 and R¹ is —CH₂—O—CH₃. In some embodiments is a compoundof Formula (III), or a pharmaceutically acceptable salt, solvate, orstereoisomer thereof, wherein m is 1 and R¹ is C₁₋₆haloalkyl. In someembodiments is a compound of Formula (III), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein m is 1 and R¹is —CF₃. In some embodiments is a compound of Formula (III), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein m is 1 and R¹ is C₃₋₈cycloalkyl. In some embodiments is acompound of Formula (III), or a pharmaceutically acceptable salt,solvate, or stereoisomer thereof, wherein m is 1 and R¹ is —NR⁵R⁶. Insome embodiments is a compound of Formula (III), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein m is 1, R¹ is—NR⁵R⁶, and R⁵ and R⁶, together with the nitrogen to which they areattached, form a heterocycloalkyl optionally substituted with one or twoR¹⁰. In some embodiments is a compound of Formula (III), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein m is 1, R¹ is —NR⁵R⁶, and R⁵ and R⁶, together with the nitrogento which they are attached, form an unsubstituted heterocycloalkyl. Insome embodiments is a compound of Formula (III), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein m is 1, R¹ is—NR⁵R⁶, and R⁵ and R⁶, together with the nitrogen to which they areattached, form a heterocycloalkyl substituted with one or two R¹⁰independently selected from C₁₋₆alkyl, C₃₋₈cycloalkyl, C₁₋₆haloalkyl,halogen, oxo, —C(O)NR⁸R⁹, —SO₂R⁸, —NR⁹C(O)R⁸, and —NR⁹SO₂R⁸. In someembodiments is a compound of Formula (III), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein m is 1, R¹ is—NR⁵R⁶, and R⁵ and R⁶, together with the nitrogen to which they areattached, form a heterocycloalkyl substituted with one or two R¹⁰independently selected from C₁₋₆alkyl, C₃₋₈cycloalkyl, and —C(O)NR⁸R⁹.In some embodiments is a compound of Formula (III), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein m is 1 and R¹ is —OR⁷. In some embodiments is a compound ofFormula (III), or a pharmaceutically acceptable salt, solvate, orstereoisomer thereof, wherein m is 1, le is —OR⁷, and R⁷ is selectedfrom C₁₋₆alkyl, C₁₋₆alkyl-O—C₁₋₆alkyl, C₁₋₆haloalkyl, C₃₋₈cycloalkyl,heterocycloalkyl, aryl, and heteroaryl. In some embodiments is acompound of Formula (III), or a pharmaceutically acceptable salt,solvate, or stereoisomer thereof, wherein m is 1 and R¹ is —OCH₃. Insome embodiments is a compound of Formula (III), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein m is 1 and R¹is —OCF₃. In some embodiments is a compound of Formula (III), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein m is 1 and R¹ is —SO₂R¹². In some embodiments is a compound ofFormula (III), or a pharmaceutically acceptable salt, solvate, orstereoisomer thereof, wherein m is 1 and R¹ is —SF₅. In some embodimentsis a compound of Formula (III), or a pharmaceutically acceptable salt,solvate, or stereoisomer thereof, wherein m is 1 and R¹ is —SR⁸. In someembodiments is a compound of Formula (III), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein m is 1 and R¹is aryl optionally substituted with one or two groups independentlyselected from halogen, C₁₋₆alkyl, C₁₋₆haloalkyl, and —C(O)NR⁸R⁹. In someembodiments is a compound of Formula (III), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein m is 1 and R¹is heteroaryl optionally substituted with one or two groupsindependently selected from halogen, C₁₋₆alkyl, C₁₋₆haloalkyl, and—C(O)NR⁸R⁹. In some embodiments is a compound of Formula (III), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein m is 1 and R¹ is selected from thiazole, pyrazine, pyrimidine,and pyridine, optionally substituted with one or two groupsindependently selected from halogen, C₁₋₆alkyl, C₁₋₆haloalkyl, and—C(O)NR⁸R⁹. In some embodiments is a compound of Formula (III), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein m is 2. In some embodiments is a compound of Formula (III), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein m is 2 and each R¹ is independently selected from halogen, —CN,C₁₋₆alkyl, C₂₋₆alkynyl, C₁₋₆alkyl-OR⁷, C₁₋₆haloalkyl, C₃₋₈cycloalkyl,—NR⁵R⁶, —OR⁷, —SO₂R¹², —SF₅, —SR⁸, aryl, and heteroaryl. In someembodiments is a compound of Formula (III), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein m is 2 andeach R¹ is independently selected from halogen, C₁₋₆alkyl,C₁₋₆haloalkyl, C₃₋₈cycloalkyl, —NR⁵R⁶, and —OR⁷. In some embodiments isa compound of Formula (III), or a pharmaceutically acceptable salt,solvate, or stereoisomer thereof, wherein m is 2 and each R¹ isindependently selected from halogen, —CN, C₁₋₆alkyl, C₁₋₆haloalkyl,—NR⁵R⁶, —OR⁷, and heteroaryl. In some embodiments is a compound ofFormula (III), or a pharmaceutically acceptable salt, solvate, orstereoisomer thereof, wherein m is 2 and each R¹ is independentlyselected from halogen, C₁₋₆haloalkyl, —NR⁵R⁶, —OR⁷, thiazole, pyrazine,pyrimidine, and pyridine. In some embodiments is a compound of Formula(III), or a pharmaceutically acceptable salt, solvate, or stereoisomerthereof, wherein m is 2 and each R¹ is independently selected fromhalogen, C₁₋₆alkyl, C₁₋₆haloalkyl, C₃₋₈cycloalkyl, and —OR⁷. In someembodiments is a compound of Formula (III), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein m is 2, eachR¹ is independently selected from halogen, C₁₋₆alkyl, C₁₋₆haloalkyl,C₃₋₈cycloalkyl, and —OR⁷, and each R⁷ is independently selected fromC₁₋₆alkyl, C₁₋₆alkyl-O—C₁₋₆alkyl, C₁₋₆haloalkyl, C₃₋₈cycloalkyl,heterocycloalkyl, aryl, and heteroaryl. In some embodiments is acompound of Formula (III), or a pharmaceutically acceptable salt,solvate, or stereoisomer thereof, wherein m is 2, each R¹ isindependently selected from halogen, C₁₋₆alkyl, C₁₋₆haloalkyl,C₃₋₈cycloalkyl, and —OR⁷, and each R⁷ is independently selected fromC₁₋₆alkyl, C₁₋₆haloalkyl, C₃₋₈cycloalkyl, and heterocycloalkyl. In someembodiments is a compound of Formula (III), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein m is 3. Insome embodiments is a compound of Formula (III), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein m is 3 andeach R¹ is independently selected from halogen, —CN, C₁₋₆alkyl,C₂₋₆alkynyl, C₁₋₆alkyl-OR⁷, C₁₋₆haloalkyl, C₃₋₈cycloalkyl, —NR⁵R⁶, —OR⁷,—SO₂R¹², —SF₅, —SR⁸, aryl, and heteroaryl. In some embodiments is acompound of Formula (III), or a pharmaceutically acceptable salt,solvate, or stereoisomer thereof, wherein m is 3 and each R¹ isindependently selected from halogen, C₁₋₆alkyl, C₁₋₆haloalkyl,C₃₋₈cycloalkyl, —NR⁵R⁶, and —OR⁷. In some embodiments is a compound ofFormula (III), or a pharmaceutically acceptable salt, solvate, orstereoisomer thereof, m is 3 and each R¹ is independently selected fromhalogen, C₁₋₆alkyl, C₁₋₆haloalkyl, C₃₋₈cycloalkyl, and —OR⁷. In someembodiments is a compound of Formula (III), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein m is 3, eachR¹ is independently selected from halogen, C₁₋₆alkyl, C₁₋₆haloalkyl,C₃₋₈cycloalkyl, and —OR⁷, and each R⁷ is independently selected fromC₁₋₆alkyl, C₁₋₆alkyl-O—C₁₋₆alkyl, C₁₋₆haloalkyl, C₃₋₈cycloalkyl,heterocycloalkyl, aryl, and heteroaryl. In some embodiments is acompound of Formula (III), or a pharmaceutically acceptable salt,solvate, or stereoisomer thereof, wherein m is 3, each R¹ isindependently selected from halogen, C₁₋₆alkyl, C₁₋₆haloalkyl,C₃₋₈cycloalkyl, and —OR⁷, and each R⁷ is independently selected fromC₁₋₆alkyl, C₁₋₆haloalkyl, C₃₋₈cycloalkyl, and heterocycloalkyl.

In some embodiments is a compound of Formula (III), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein n is 0. In some embodiments is a compound of Formula (III), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein n is 1. In some embodiments is a compound of Formula (III), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein n is 1 and R¹ is selected from halogen, —CN, C₁₋₆alkyl,C₂₋₆alkynyl, C₁₋₆alkyl-OR⁷, C₁₋₆haloalkyl, C₃₋₈cycloalkyl, —NR⁵R⁶, —OR⁷,—SO₂R¹², —SF₅, —SR⁸, aryl, and heteroaryl. In some embodiments is acompound of Formula (III), or a pharmaceutically acceptable salt,solvate, or stereoisomer thereof, wherein n is 1 and R¹ is selected fromhalogen, C₁₋₆alkyl, C₁₋₆haloalkyl, C₃₋₈cycloalkyl, —NR⁵R⁶, and —OR⁷. Insome embodiments is a compound of Formula (III), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein n is 1 and R¹is selected from halogen, C₁₋₆alkyl, C₁₋₆haloalkyl, C₃₋₈cycloalkyl, and—OR⁷. In some embodiments is a compound of Formula (III), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein n is 1 and R¹ is halogen. In some embodiments is a compound ofFormula (III), or a pharmaceutically acceptable salt, solvate, orstereoisomer thereof, wherein n is 1 and R¹ is F. In some embodiments isa compound of Formula (III), or a pharmaceutically acceptable salt,solvate, or stereoisomer thereof, wherein n is 1 and R¹ is Cl. In someembodiments is a compound of Formula (III), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein n is 1 and R¹is —CN. In some embodiments is a compound of Formula (III), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein n is 1 and R¹ is C₁₋₆alkyl. In some embodiments is a compound ofFormula (III), or a pharmaceutically acceptable salt, solvate, orstereoisomer thereof, wherein n is 1 and R¹ is —CH₃. In some embodimentsis a compound of Formula (III), or a pharmaceutically acceptable salt,solvate, or stereoisomer thereof, wherein n is 1 and R′ is —C≡CH In someembodiments is a compound of Formula (III), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein n is 1 and R¹is C₁₋₆alkyl-OR⁷. In some embodiments is a compound of Formula (III), ora pharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein n is 1 and R¹ is —CH₂—O—CH₃. In some embodiments is a compoundof Formula (III), or a pharmaceutically acceptable salt, solvate, orstereoisomer thereof, wherein n is 1 and R¹ is C₁₋₆haloalkyl. In someembodiments is a compound of Formula (III), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein n is 1 and R¹is —CF₃. In some embodiments is a compound of Formula (III), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein n is 1 and R¹ is C₃₋₈cycloalkyl. In some embodiments is acompound of Formula (III), or a pharmaceutically acceptable salt,solvate, or stereoisomer thereof, wherein n is 1 and R¹ is —NR⁵R⁶. Insome embodiments is a compound of Formula (III), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein n is 1, R¹ is—NR⁵R⁶, and R⁵ and R⁶, together with the nitrogen to which they areattached, form a heterocycloalkyl optionally substituted with one or twoR¹⁰. In some embodiments is a compound of Formula (III), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein n is 1, R¹ is —NR⁵R⁶, and R⁵ and R⁶, together with the nitrogento which they are attached, form an unsubstituted heterocycloalkyl. Insome embodiments is a compound of Formula (III), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein n is 1, R¹ is—NR⁵R⁶, and R⁵ and R⁶, together with the nitrogen to which they areattached, form a heterocycloalkyl substituted with one or two R¹⁰independently selected from C₁₋₆alkyl, C₃₋₈cycloalkyl, C₁₋₆haloalkyl,halogen, oxo, —C(O)NR⁸R⁹, —SO₂R⁸, —NR⁹C(O)R⁸, and —NR⁹SO₂R⁸. In someembodiments is a compound of Formula (III), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein n is 1, R¹ is—NR⁵R⁶, and R⁵ and R⁶, together with the nitrogen to which they areattached, form a heterocycloalkyl substituted with one or two R¹⁰independently selected from C₁₋₆alkyl, C₃₋₈cycloalkyl, and —C(O)NR⁸R⁹.In some embodiments is a compound of Formula (III), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein n is 1 and R¹ is —OR⁷. In some embodiments is a compound ofFormula (III), or a pharmaceutically acceptable salt, solvate, orstereoisomer thereof, wherein n is 1, le is —OR⁷, and R⁷ is selectedfrom C₁₋₆alkyl, C₁₋₆alkyl-O—C₁₋₆alkyl, C₁₋₆haloalkyl, C₃₋₈cycloalkyl,heterocycloalkyl, aryl, and heteroaryl. In some embodiments is acompound of Formula (III), or a pharmaceutically acceptable salt,solvate, or stereoisomer thereof, wherein n is 1 and R¹ is —OCH₃. Insome embodiments is a compound of Formula (III), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein n is 1 and R¹is —OCF₃. In some embodiments is a compound of Formula (III), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein n is 1 and R¹ is —SO₂R¹². In some embodiments is a compound ofFormula (III), or a pharmaceutically acceptable salt, solvate, orstereoisomer thereof, wherein n is 1 and R¹ is —SF₅. In some embodimentsis a compound of Formula (III), or a pharmaceutically acceptable salt,solvate, or stereoisomer thereof, wherein n is 1 and R¹ is —SR⁸. In someembodiments is a compound of Formula (III), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein n is 1 and R¹is aryl optionally substituted with one or two groups independentlyselected from halogen, C₁₋₆alkyl, C₁₋₆haloalkyl, and —C(O)NR⁸R⁹. In someembodiments is a compound of Formula (III), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein n is 1 and R¹is heteroaryl optionally substituted with one or two groupsindependently selected from halogen, C₁₋₆alkyl, C₁₋₆haloalkyl, and—C(O)NR⁸R⁹. In some embodiments is a compound of Formula (III), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein n is 1 and R¹ is selected from thiazole, pyrazine, pyrimidine,and pyridine, optionally substituted with one or two groupsindependently selected from halogen, C₁₋₆alkyl, C₁₋₆haloalkyl, and—C(O)NR⁸R⁹. In some embodiments is a compound of Formula (III), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein n is 2. In some embodiments is a compound of Formula (III), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein n is 2 and each R¹ is independently selected from halogen, —CN,C₁₋₆alkyl, C₂₋₆alkynyl, C₁₋₆alkyl-OR⁷, C₁₋₆haloalkyl, C₃₋₈cycloalkyl,—NR⁵R⁶, —SO₂R¹², —SF₅, —SR⁸, aryl, and heteroaryl. In some embodimentsis a compound of Formula (III), or a pharmaceutically acceptable salt,solvate, or stereoisomer thereof, wherein n is 2 and each R¹ isindependently selected from halogen, C₁₋₆alkyl, C₁₋₆haloalkyl,C₃₋₈cycloalkyl, —NR⁵R⁶, and —OR⁷. In some embodiments is a compound ofFormula (III), or a pharmaceutically acceptable salt, solvate, orstereoisomer thereof, wherein n is 2 and each R¹ is independentlyselected from halogen, —CN, C₁₋₆alkyl, C₁₋₆haloalkyl, —NR⁵R⁶, —OR⁷, andheteroaryl. In some embodiments is a compound of Formula (III), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein n is 2 and each R¹ is independently selected from halogen,C₁₋₆haloalkyl, —NR⁵R⁶, thiazole, pyrazine, pyrimidine, and pyridine. Insome embodiments is a compound of Formula (III), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein n is 2 andeach R¹ is independently selected from halogen, C₁₋₆alkyl,C₁₋₆haloalkyl, C₃₋₈cycloalkyl, and —OR⁷. In some embodiments is acompound of Formula (III), or a pharmaceutically acceptable salt,solvate, or stereoisomer thereof, wherein n is 2, each R¹ isindependently selected from halogen, C₁₋₆alkyl, C₁₋₆haloalkyl,C₃₋₈cycloalkyl, and —OR⁷, and each R⁷ is independently selected fromC₁₋₆alkyl, C₁₋₆alkyl-O—C₁₋₆alkyl, C₁₋₆haloalkyl, C₃₋₈cycloalkyl,heterocycloalkyl, aryl, and heteroaryl. In some embodiments is acompound of Formula (III), or a pharmaceutically acceptable salt,solvate, or stereoisomer thereof, wherein n is 2, each R¹ isindependently selected from halogen, C₁₋₆alkyl, C₁₋₆haloalkyl,C₃₋₈cycloalkyl, and —OR⁷, and each R⁷ is independently selected fromC₁₋₆alkyl, C₁₋₆haloalkyl, C₃₋₈cycloalkyl, and heterocycloalkyl. In someembodiments is a compound of Formula (III), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein n is 3.

In some embodiments is a compound of Formula

wherein:

-   each R¹ is independently selected from halogen, —CN, C₁₋₆alkyl,    C₂₋₆alkynyl, C₁₋₆alkyl-OR⁷, C₁₋₆haloalkyl, C₃₋₈cycloalkyl, —NR⁵R⁶,    —C(O)NR⁵R⁶, —OR⁷, —SO₂R¹², —SF₅, —SR⁸, aryl, and heteroaryl, wherein    aryl and heteroaryl are optionally substituted with one or two    groups independently selected from halogen, C₁₋₆alkyl,    C₁₋₆haloalkyl, and —C(O)NR⁸R⁹; or two adjacent R¹ form a    heterocycloalkyl ring optionally substituted with one or two R¹¹;-   R³ is selected from halogen, —CN, C₁₋₆alkyl, C₁₋₆haloalkyl, —NR⁸R⁹,    —C(O)NR⁸R⁹, —NR⁸C(O)R⁹, and —NR⁹SO₂R⁸;-   R^(3a) is selected from halogen, C₁₋₆alkyl, and C₁₋₆haloalkyl;-   each R⁵ and R⁶ is independently selected from H, C₁₋₆alkyl, and    C₃₋₈cycloalkyl; or R⁵ and R⁶, together with the nitrogen to which    they are attached, form a heterocycloalkyl optionally substituted    with one or two R¹⁰;-   each R⁷ is independently selected from H, C₁₋₆alkyl,    C₁₋₆alkyl-O—C₁₋₆alkyl, C₁₋₆haloalkyl, C₃₋₈cycloalkyl,    heterocycloalkyl, aryl, and heteroaryl, wherein heterocycloalkyl,    aryl, and heteroaryl are optionally substituted with one or two    groups independently selected from halogen, C₁₋₆alkyl, and    C₁₋₆haloalkyl;-   each R⁸ and R⁹ is independently selected from H, C₁₋₆alkyl,    C₃₋₈cycloalkyl, aryl, and heteroaryl;-   each R¹⁰ is independently selected from C₁₋₆alkyl, C₃₋₈cycloalkyl,    C₁₋₆haloalkyl, halogen, oxo, —CN, —C(O)OR⁸, —C(O)R⁸, —C(O)NR⁸R⁹,    —SO₂R⁸, —NR⁹C(O)R⁸, and —NR⁹SO₂R⁸;-   each R¹¹ is independently selected from halogen and C₁₋₆alkyl;-   each R¹² is independently selected from C₁₋₆alkyl and    C₃₋₈cycloalkyl;-   m is 0, 1, 2, 3, 4, or 5; and-   q is 0 or 1;    or a pharmaceutically acceptable salt, solvate, or stereoisomer    thereof.

In some embodiments is a compound of Formula (IIIa), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein R³ is halogen. In some embodiments is a compound of Formula(IIIa), or a pharmaceutically acceptable salt, solvate, or stereoisomerthereof, wherein R³ is —CN. In some embodiments is a compound of Formula(IIIa), or a pharmaceutically acceptable salt, solvate, or stereoisomerthereof, wherein R³ is C₁₋₆alkyl. In some embodiments is a compound ofFormula (IIIa), or a pharmaceutically acceptable salt, solvate, orstereoisomer thereof, wherein R³ is —CH₃. In some embodiments is acompound of Formula (IIIa), or a pharmaceutically acceptable salt,solvate, or stereoisomer thereof, wherein R³ is C₁₋₆haloalkyl. In someembodiments is a compound of Formula (IIIa), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein R³ is —CF₃.In some embodiments is a compound of Formula (IIIa), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein R³ is —NR⁸R⁹. In some embodiments is a compound of Formula(IIIa), or a pharmaceutically acceptable salt, solvate, or stereoisomerthereof, wherein R³ is —NH₂. In some embodiments is a compound ofFormula (IIIa), or a pharmaceutically acceptable salt, solvate, orstereoisomer thereof, wherein R³ is —C(O)NR⁸R⁹. In some embodiments is acompound of Formula (IIIa), or a pharmaceutically acceptable salt,solvate, or stereoisomer thereof, wherein R³ is —C(O)NH₂. In someembodiments is a compound of Formula (IIIa), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein R³ is—NR⁸C(O)R⁹. In some embodiments is a compound of Formula (IIIa), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein R³ is —NHC(O)CH₃. In some embodiments is a compound of Formula(IIIa), or a pharmaceutically acceptable salt, solvate, or stereoisomerthereof, wherein q is 0. In some embodiments is a compound of Formula(IIIa), or a pharmaceutically acceptable salt, solvate, or stereoisomerthereof, wherein q is 1. In some embodiments is a compound of Formula(IIIa), or a pharmaceutically acceptable salt, solvate, or stereoisomerthereof, wherein q is 1 and R^(3a) is halogen. In some embodiments is acompound of Formula (IIIa), or a pharmaceutically acceptable salt,solvate, or stereoisomer thereof, wherein q is 1 and R^(3a) isC₁₋₆alkyl. In some embodiments is a compound of Formula (IIIa), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein q is 1 and R^(3a) is C₁₋₆haloalkyl.

In some embodiments is a compound of Formula (IIIa), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein m is 0. In some embodiments is a compound of Formula (IIIa), ora pharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein m is 1. In some embodiments is a compound of Formula (IIIa), ora pharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein m is 1 and R¹ is selected from halogen, —CN, C₁₋₆alkyl,C₂-6alkynyl, C₁₋₆alkyl-OR⁷, C₁₋₆haloalkyl, C₃₋₈cycloalkyl, —NR⁵R⁶, —OR⁷,—SO₂R¹², —SF₅, —SR⁸, aryl, and heteroaryl. In some embodiments is acompound of Formula (IIIa), or a pharmaceutically acceptable salt,solvate, or stereoisomer thereof, wherein m is 1 and R¹ is selected fromhalogen, C₁₋₆alkyl, C₁₋₆haloalkyl, C₃₋₈cycloalkyl, —NR⁵R⁶, and —OR⁷. Insome embodiments is a compound of Formula (IIIa), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein m is 1 and R¹is selected from halogen, C₁₋₆alkyl, C₁₋₆haloalkyl, C₃₋₈cycloalkyl, and—OR⁷. In some embodiments is a compound of Formula (IIIa), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein m is 1 and R¹ is halogen. In some embodiments is a compound ofFormula (IIIa), or a pharmaceutically acceptable salt, solvate, orstereoisomer thereof, wherein m is 1 and R¹ is F. In some embodiments isa compound of Formula (IIIa), or a pharmaceutically acceptable salt,solvate, or stereoisomer thereof, wherein m is 1 and R¹ is Cl. In someembodiments is a compound of Formula (IIIa), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein m is 1 and R¹is —CN. In some embodiments is a compound of Formula (IIIa), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein m is 1 and R¹ is C₁₋₆alkyl. In some embodiments is a compound ofFormula (IIIa), or a pharmaceutically acceptable salt, solvate, orstereoisomer thereof, wherein m is 1 and R¹ is —CH₃. In some embodimentsis a compound of Formula (IIIa), or a pharmaceutically acceptable salt,solvate, or stereoisomer thereof, wherein m is 1 and R¹ is —C≡CH. Insome embodiments is a compound of Formula (IIIa), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein m is 1 and R¹is C₁₋₆alkyl-OR⁷. In some embodiments is a compound of Formula (IIIa),or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein m is 1 and R¹ is —CH₂—O—CH₃. In some embodiments is a compoundof Formula (IIIa), or a pharmaceutically acceptable salt, solvate, orstereoisomer thereof, wherein m is 1 and R¹ is C₁₋₆haloalkyl. In someembodiments is a compound of Formula (IIIa), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein m is 1 and R¹is —CF₃. In some embodiments is a compound of Formula (IIIa), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein m is 1 and R¹ is C₃₋₈cycloalkyl. In some embodiments is acompound of Formula (IIIa), or a pharmaceutically acceptable salt,solvate, or stereoisomer thereof, wherein m is 1 and R¹ is —NR⁵R⁶. Insome embodiments is a compound of Formula (IIIa), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein m is 1, R¹ is—NR⁵R⁶, and R⁵ and R⁶, together with the nitrogen to which they areattached, form a heterocycloalkyl optionally substituted with one or twoR¹⁰. In some embodiments is a compound of Formula (IIIa), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein m is 1, R¹ is —NR⁵R⁶, and R⁵ and R⁶, together with the nitrogento which they are attached, form an unsubstituted heterocycloalkyl. Insome embodiments is a compound of Formula (IIIa), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein m is 1, R¹ is—NR⁵R⁶, and R⁵ and R⁶, together with the nitrogen to which they areattached, form a heterocycloalkyl substituted with one or two R¹⁰independently selected from C₁₋₆alkyl, C₃₋₈cycloalkyl, C₁₋₆haloalkyl,halogen, oxo, —C(O)NR⁸R⁹, —SO₂R⁸, —NR⁹C(O)R⁸, and —NR⁹SO₂R⁸. In someembodiments is a compound of Formula (IIIa), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein m is 1, R¹ is—NR⁵R⁶, and R⁵ and R⁶, together with the nitrogen to which they areattached, form a heterocycloalkyl substituted with one or two R¹⁰independently selected from C₁₋₆alkyl, C₃₋₈cycloalkyl, and —C(O)NR⁸R⁹.In some embodiments is a compound of Formula (IIIa), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein m is 1 and R¹ is —OR⁷. In some embodiments is a compound ofFormula (IIIa), or a pharmaceutically acceptable salt, solvate, orstereoisomer thereof, wherein m is 1, le is —OR⁷, and R⁷ is selectedfrom C₁₋₆alkyl, C₁₋₆haloalkyl, C₃₋₈cycloalkyl, heterocycloalkyl, aryl,and heteroaryl. In some embodiments is a compound of Formula (IIIa), ora pharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein m is 1 and R¹ is —OCH₃. In some embodiments is a compound ofFormula (IIIa), or a pharmaceutically acceptable salt, solvate, orstereoisomer thereof, wherein m is 1 and R¹ is —OCF₃. In someembodiments is a compound of Formula (IIIa), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein m is 1 and R¹is —SO₂R¹². In some embodiments is a compound of Formula (IIIa), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein m is 1 and R¹ is —SF₅. In some embodiments is a compound ofFormula (IIIa), or a pharmaceutically acceptable salt, solvate, orstereoisomer thereof, wherein m is 1 and R¹ is —SR⁸. In some embodimentsis a compound of Formula (IIIa), or a pharmaceutically acceptable salt,solvate, or stereoisomer thereof, wherein m is 1 and R¹ is aryloptionally substituted with one or two groups independently selectedfrom halogen, C₁₋₆alkyl, C₁₋₆haloalkyl, and —C(O)NR⁸R⁹. In someembodiments is a compound of Formula (IIIa), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein m is 1 and R¹is heteroaryl optionally substituted with one or two groupsindependently selected from halogen, C₁₋₆alkyl, C₁₋₆haloalkyl, and—C(O)NR⁸R⁹. In some embodiments is a compound of Formula (IIIa), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein m is 1 and R¹ is selected from thiazole, pyrazine, pyrimidine,and pyridine, optionally substituted with one or two groupsindependently selected from halogen, C₁₋₆alkyl, C₁₋₆haloalkyl, and—C(O)NR⁸R⁹. In some embodiments is a compound of Formula (IIIa), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein m is 2. In some embodiments is a compound of Formula (IIIa), ora pharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein m is 2 and each R¹ is independently selected from halogen, —CN,C₁₋₆alkyl, C₂₋₆alkynyl, C₁₋₆alkyl-OR⁷, C₁₋₆haloalkyl, C₃₋₈cycloalkyl,—NR⁵R⁶, —OR⁷, —SO₂R¹², —SF₅, —SR⁸, aryl, and heteroaryl. In someembodiments is a compound of Formula (IIIa), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein m is 2 andeach R¹ is independently selected from halogen, C₁₋₆alkyl,C₁₋₆haloalkyl, C₃₋₈cycloalkyl, —NR⁵R⁶, and —OR⁷. In some embodiments isa compound of Formula (IIIa), or a pharmaceutically acceptable salt,solvate, or stereoisomer thereof, wherein m is 2 and each R¹ isindependently selected from halogen, —CN, C₁₋₆alkyl, C₁₋₆haloalkyl,—NR⁵R⁶, —OR⁷, and heteroaryl. In some embodiments is a compound ofFormula (IIIa), or a pharmaceutically acceptable salt, solvate, orstereoisomer thereof, wherein m is 2 and each R¹ is independentlyselected from halogen, C₁₋₆haloalkyl, —NR⁵R⁶, —OR⁷, thiazole, pyrazine,pyrimidine, and pyridine. In some embodiments is a compound of Formula(IIIa), or a pharmaceutically acceptable salt, solvate, or stereoisomerthereof, wherein m is 2 and each R¹ is independently selected fromhalogen, C₁₋₆alkyl, C₁₋₆haloalkyl, C₃₋₈cycloalkyl, and —OR⁷. In someembodiments is a compound of Formula (IIIa), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein m is 2, eachR¹ is independently selected from halogen, C₁₋₆alkyl, C₁₋₆haloalkyl,C₃₋₈cycloalkyl, and —OR⁷, and each R⁷ is independently selected fromC₁₋₆alkyl, C₁₋₆alkyl-O—C₁₋₆alkyl, C₁₋₆haloalkyl, C₃₋₈cycloalkyl,heterocycloalkyl, aryl, and heteroaryl. In some embodiments is acompound of Formula (IIIa), or a pharmaceutically acceptable salt,solvate, or stereoisomer thereof, wherein m is 2, each R¹ isindependently selected from halogen, C₁₋₆alkyl, C₁₋₆haloalkyl,C₃₋₈cycloalkyl, and —OR⁷, and each R⁷ is independently selected fromC₁₋₆alkyl, C₁₋₆haloalkyl, C₃₋₈cycloalkyl, and heterocycloalkyl. In someembodiments is a compound of Formula (IIIa), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein m is 3. Insome embodiments is a compound of Formula (IIIa), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein m is 3 andeach R¹ is independently selected from halogen, —CN, C₁₋₆alkyl,C₂₋₆alkynyl, C₁₋₆alkyl-OR⁷, C₁₋₆haloalkyl, C₃₋₈cycloalkyl, —NR⁵R⁶, —OR⁷,—SO₂R¹², —SF₅, —SR⁸, aryl, and heteroaryl. In some embodiments is acompound of Formula (IIIa), or a pharmaceutically acceptable salt,solvate, or stereoisomer thereof, wherein m is 3 and each R¹ isindependently selected from halogen, C₁₋₆alkyl, C₁₋₆haloalkyl,C₃₋₈cycloalkyl, —NR⁵R⁶, and —OR⁷. In some embodiments is a compound ofFormula (IIIa), or a pharmaceutically acceptable salt, solvate, orstereoisomer thereof, m is 3 and each R¹ is independently selected fromhalogen, C₁₋₆alkyl, C₁₋₆haloalkyl, C₃₋₈cycloalkyl, and —OR⁷. In someembodiments is a compound of Formula (IIIa), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein m is 3, eachR¹ is independently selected from halogen, C₁₋₆alkyl, C₁₋₆haloalkyl,C₃₋₈cycloalkyl, and —OR⁷, and each R⁷ is independently selected fromC₁₋₆alkyl, C₁₋₆alkyl-O—C₁₋₆alkyl, C₁₋₆haloalkyl, C₃₋₈cycloalkyl,heterocycloalkyl, aryl, and heteroaryl. In some embodiments is acompound of Formula (IIIa), or a pharmaceutically acceptable salt,solvate, or stereoisomer thereof, wherein m is 3, each R¹ isindependently selected from halogen, C₁₋₆alkyl, C₁₋₆haloalkyl,C₃₋₈cycloalkyl, and —OR⁷, and each R⁷ is independently selected fromC₁₋₆alkyl, C₁₋₆haloalkyl, C₃₋₈cycloalkyl, and heterocycloalkyl.

In some embodiments is a compound of Formula (IIIa), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein n is 0. In some embodiments is a compound of Formula (IIIa), ora pharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein n is 1. In some embodiments is a compound of Formula (IIIa), ora pharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein n is 1 and R¹ is selected from halogen, —CN, C₁₋₆alkyl,C₂-6alkynyl, C₁₋₆alkyl-OR⁷, C₁₋₆haloalkyl, C₃₋₈cycloalkyl, —NR⁵R⁶, —OR⁷,—SO₂R¹², —SF₅, —SR⁸, aryl, and heteroaryl. In some embodiments is acompound of Formula (IIIa), or a pharmaceutically acceptable salt,solvate, or stereoisomer thereof, wherein n is 1 and R¹ is selected fromhalogen, C₁₋₆alkyl, C₁₋₆haloalkyl, C₃₋₈cycloalkyl, —NR⁵R⁶, and —OR⁷. Insome embodiments is a compound of Formula (IIIa), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein n is 1 and R¹is selected from halogen, C₁₋₆alkyl, C₁₋₆haloalkyl, C₃₋₈cycloalkyl, and—OR⁷. In some embodiments is a compound of Formula (IIIa), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein n is 1 and R¹ is halogen. In some embodiments is a compound ofFormula (IIIa), or a pharmaceutically acceptable salt, solvate, orstereoisomer thereof, wherein n is 1 and R¹ is F. In some embodiments isa compound of Formula (IIIa), or a pharmaceutically acceptable salt,solvate, or stereoisomer thereof, wherein n is 1 and R¹ is Cl. In someembodiments is a compound of Formula (IIIa), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein n is 1 and R¹is —CN. In some embodiments is a compound of Formula (IIIa), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein n is 1 and R¹ is C₁₋₆alkyl. In some embodiments is a compound ofFormula (IIIa), or a pharmaceutically acceptable salt, solvate, orstereoisomer thereof, wherein n is 1 and R¹ is —CH₃. In some embodimentsis a compound of Formula (IIIa), or a pharmaceutically acceptable salt,solvate, or stereoisomer thereof, wherein n is 1 and R¹ is —C≡CH. Insome embodiments is a compound of Formula (IIIa), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein n is 1 and R¹is C₁₋₆alkyl-OR⁷. In some embodiments is a compound of Formula (IIIa),or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein n is 1 and R¹ is —CH₂—O—CH₃. In some embodiments is a compoundof Formula (IIIa), or a pharmaceutically acceptable salt, solvate, orstereoisomer thereof, wherein n is 1 and R¹ is C₁₋₆haloalkyl. In someembodiments is a compound of Formula (IIIa), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein n is 1 and R¹is —CF₃. In some embodiments is a compound of Formula (IIIa), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein n is 1 and R¹ is C₃₋₈cycloalkyl. In some embodiments is acompound of Formula (IIIa), or a pharmaceutically acceptable salt,solvate, or stereoisomer thereof, wherein n is 1 and R¹ is —NR⁵R⁶. Insome embodiments is a compound of Formula (IIIa), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein n is 1, R¹ is—NR⁵R⁶, and R⁵ and R⁶, together with the nitrogen to which they areattached, form a heterocycloalkyl optionally substituted with one or twoR¹⁰. In some embodiments is a compound of Formula (IIIa), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein n is 1, R¹ is —NR⁵R⁶, and R⁵ and R⁶, together with the nitrogento which they are attached, form an unsubstituted heterocycloalkyl. Insome embodiments is a compound of Formula (IIIa), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein n is 1, R¹ is—NR⁵R⁶, and R⁵ and R⁶, together with the nitrogen to which they areattached, form a heterocycloalkyl substituted with one or two R¹⁰independently selected from C₁₋₆alkyl, C₃₋₈cycloalkyl, C₁₋₆haloalkyl,halogen, oxo, —C(O)NR⁸R⁹, —SO₂R⁸, —NR⁹C(O)R⁸, and —NR⁹SO₂R⁸. In someembodiments is a compound of Formula (IIIa), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein n is 1, R¹ is—NR⁵R⁶, and R⁵ and R⁶, together with the nitrogen to which they areattached, form a heterocycloalkyl substituted with one or two R¹⁰independently selected from C₁₋₆alkyl, C₃₋₈cycloalkyl, and —C(O)NR⁸R⁹.In some embodiments is a compound of Formula (IIIa), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein n is 1 and R¹ is —OR⁷. In some embodiments is a compound ofFormula (IIIa), or a pharmaceutically acceptable salt, solvate, orstereoisomer thereof, wherein n is 1, R¹ is —OW, and R⁷ is selected fromC₁₋₆alkyl, C₁₋₆alkyl-O—C₁₋₆alkyl, C₁₋₆haloalkyl, C₃₋₈cycloalkyl,heterocycloalkyl, aryl, and heteroaryl. In some embodiments is acompound of Formula (IIIa), or a pharmaceutically acceptable salt,solvate, or stereoisomer thereof, wherein n is 1 and R¹ is —OCH₃. Insome embodiments is a compound of Formula (IIIa), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein n is 1 and R¹is —OCF₃. In some embodiments is a compound of Formula (IIIa), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein n is 1 and R¹ is —SO₂R¹². In some embodiments is a compound ofFormula (IIIa), or a pharmaceutically acceptable salt, solvate, orstereoisomer thereof, wherein n is 1 and R¹ is —SF₅. In some embodimentsis a compound of Formula (IIIa), or a pharmaceutically acceptable salt,solvate, or stereoisomer thereof, wherein n is 1 and R¹ is —SR⁸. In someembodiments is a compound of Formula (IIIa), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein n is 1 and R¹is aryl optionally substituted with one or two groups independentlyselected from halogen, C₁₋₆alkyl, C₁₋₆haloalkyl, and —C(O)NR⁸R⁹. In someembodiments is a compound of Formula (IIIa), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein n is 1 and R¹is heteroaryl optionally substituted with one or two groupsindependently selected from halogen, C₁₋₆alkyl, C₁₋₆haloalkyl, and—C(O)NR⁸R⁹. In some embodiments is a compound of Formula (IIIa), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein n is 1 and R¹ is selected from thiazole, pyrazine, pyrimidine,and pyridine, optionally substituted with one or two groupsindependently selected from halogen, C₁₋₆alkyl, C₁₋₆haloalkyl, and—C(O)NR⁸R⁹. In some embodiments is a compound of Formula (IIIa), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein n is 2. In some embodiments is a compound of Formula (IIIa), ora pharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein n is 2 and each R¹ is independently selected from halogen, —CN,C₁₋₆alkyl, C₂₋₆alkynyl, C₁₋₆alkyl-OR⁷, C₁₋₆haloalkyl, C₃₋₈cycloalkyl,—NR⁵R⁶, —OR⁷, —SO₂R¹², —SF₅, —SR⁸, aryl, and heteroaryl. In someembodiments is a compound of Formula (IIIa), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein n is 2 andeach R¹ is independently selected from halogen, C₁₋₆alkyl,C₁₋₆haloalkyl, C₃₋₈cycloalkyl, —NR⁵R⁶, and —OR⁷. In some embodiments isa compound of Formula (IIIa), or a pharmaceutically acceptable salt,solvate, or stereoisomer thereof, wherein n is 2 and each R¹ isindependently selected from halogen, —CN, C₁₋₆alkyl, C₁₋₆haloalkyl,—NR⁵R⁶, —OR⁷, and heteroaryl. In some embodiments is a compound ofFormula (IIIa), or a pharmaceutically acceptable salt, solvate, orstereoisomer thereof, wherein n is 2 and each R¹ is independentlyselected from halogen, 6haloalkyl, —NR⁵R⁶, —OR⁷, thiazole, pyrazine,pyrimidine, and pyridine. In some embodiments is a compound of Formula(IIIa), or a pharmaceutically acceptable salt, solvate, or stereoisomerthereof, wherein n is 2 and each R¹ is independently selected fromhalogen, C₁₋₆alkyl, C₁₋₆haloalkyl, C₃₋₈cycloalkyl, and —OR⁷. In someembodiments is a compound of Formula (IIIa), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein n is 2, eachR¹ is independently selected from halogen, C₁₋₆alkyl, C₁₋₆haloalkyl,C₃₋₈cycloalkyl, and —OR⁷, and each R⁷ is independently selected fromC₁₋₆alkyl, C₁₋₆haloalkyl, C₃₋₈cycloalkyl, heterocycloalkyl, aryl, andheteroaryl. In some embodiments is a compound of Formula (IIIa), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein n is 2, each R¹ is independently selected from halogen,C₁₋₆alkyl, C₁₋₆haloalkyl, C₃₋₈cycloalkyl, and —OR⁷, and each R⁷ isindependently selected from C₁₋₆alkyl, C₁₋₆haloalkyl, C₃₋₈cycloalkyl,and heterocycloalkyl. In some embodiments is a compound of Formula(IIIa), or a pharmaceutically acceptable salt, solvate, or stereoisomerthereof, wherein n is 3.

In some embodiments is a compound of Formula (IIIb):

wherein:

-   each R¹ is independently selected from halogen, —CN, C₁₋₆alkyl,    C₂₋₆alkynyl, C₁₋₆alkyl-OR⁷, C₁₋₆haloalkyl, C₃₋₈cycloalkyl, —NR⁵R⁶,    —C(O)NR⁵R⁶, —OR⁷, —SO₂R¹², —SF₅, —SR⁸, aryl, and heteroaryl, wherein    aryl and heteroaryl are optionally substituted with one or two    groups independently selected from halogen, C₁₋₆alkyl,    C₁₋₆haloalkyl, and —C(O)NR⁸R⁹; or two adjacent R¹ form a    heterocycloalkyl ring optionally substituted with one or two R¹¹;-   R³ is selected from halogen, —CN, C₁₋₆alkyl, C₁₋₆haloalkyl, —NR⁸R⁹,    —C(O)NR⁸R⁹, —NR⁸C(O)R⁹, and —NR⁹SO₂R⁸;-   R^(3a) is selected from halogen, C₁₋₆alkyl, and C₁₋₆haloalkyl;-   each R⁵ and R⁶ is independently selected from H, C₁₋₆alkyl, and    C₃₋₈cycloalkyl; or R⁵ and R⁶, together with the nitrogen to which    they are attached, form a heterocycloalkyl optionally substituted    with one or two R¹⁰;-   each R⁷ is independently selected from H, C₁₋₆alkyl,    C₁₋₆alkyl-O—C₁₋₆alkyl, C₁₋₆haloalkyl, C₃₋₈cycloalkyl,    heterocycloalkyl, aryl, and heteroaryl, wherein heterocycloalkyl,    aryl, and heteroaryl are optionally substituted with one or two    groups independently selected from halogen, C₁₋₆alkyl, and    C₁₋₆haloalkyl;-   each R⁸ and R⁹ is independently selected from H, C₁₋₆alkyl,    C₃₋₈cycloalkyl, aryl, and heteroaryl;-   each R¹⁰ is independently selected from C₁₋₆alkyl, C₃₋₈cycloalkyl,    C₁₋₆haloalkyl, halogen, oxo, —CN, —C(O)OR⁸, —C(O)R⁸, —C(O)NR⁸R⁹,    —SO₂R⁸, —NR⁹C(O)R⁸, and —NR⁹SO₂R⁸;-   each R¹¹ is independently selected from halogen and C₁₋₆alkyl;-   each R¹² is independently selected from C₁₋₆alkyl and    C₃₋₈cycloalkyl;-   m is 0, 1, 2, 3, 4, or 5; and-   q is 0 or 1;    or a pharmaceutically acceptable salt, solvate, or stereoisomer    thereof.

In some embodiments is a compound of Formula (IIIb), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein R³ is halogen. In some embodiments is a compound of Formula(IIIb), or a pharmaceutically acceptable salt, solvate, or stereoisomerthereof, wherein R³ is —CN. In some embodiments is a compound of Formula(IIIb), or a pharmaceutically acceptable salt, solvate, or stereoisomerthereof, wherein R³ is C₁₋₆alkyl. In some embodiments is a compound ofFormula (IIIb), or a pharmaceutically acceptable salt, solvate, orstereoisomer thereof, wherein R³ is —CH₃. In some embodiments is acompound of Formula (IIIb), or a pharmaceutically acceptable salt,solvate, or stereoisomer thereof, wherein R³ is C₁₋₆haloalkyl. In someembodiments is a compound of Formula (IIIb), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein R³ is —CF₃.In some embodiments is a compound of Formula (IIIb), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein R³ is —NR⁸R⁹. In some embodiments is a compound of Formula(IIIb), or a pharmaceutically acceptable salt, solvate, or stereoisomerthereof, wherein R³ is —NH₂. In some embodiments is a compound ofFormula (IIIb), or a pharmaceutically acceptable salt, solvate, orstereoisomer thereof, wherein R³ is —C(O)NR⁸R⁹. In some embodiments is acompound of Formula (IIIb), or a pharmaceutically acceptable salt,solvate, or stereoisomer thereof, wherein R³ is —C(O)NH₂. In someembodiments is a compound of Formula (IIIb), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein R³ is—NR⁸C(O)R⁹. In some embodiments is a compound of Formula (IIIb), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein R³ is —NHC(O)CH₃. In some embodiments is a compound of Formula(IIIb), or a pharmaceutically acceptable salt, solvate, or stereoisomerthereof, wherein q is 0. In some embodiments is a compound of Formula(IIIb), or a pharmaceutically acceptable salt, solvate, or stereoisomerthereof, wherein q is 1. In some embodiments is a compound of Formula(IIIb), or a pharmaceutically acceptable salt, solvate, or stereoisomerthereof, wherein q is 1 and R^(3a) is halogen. In some embodiments is acompound of Formula (IIIb), or a pharmaceutically acceptable salt,solvate, or stereoisomer thereof, wherein q is 1 and R^(3a) isC₁₋₆alkyl. In some embodiments is a compound of Formula (IIIb), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein q is 1 and R^(3a) is C₁₋₆haloalkyl.

In some embodiments is a compound of Formula (IIIb), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein m is 0. In some embodiments is a compound of Formula (IIIb), ora pharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein m is 1. In some embodiments is a compound of Formula (IIIb), ora pharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein m is 1 and R¹ is selected from halogen, —CN, C₁₋₆alkyl,C₂-6alkynyl, C₁₋₆alkyl-OR⁷, C₁₋₆haloalkyl, C₃₋₈cycloalkyl, —NR⁵R⁶, —OR⁷,—SO₂R¹², —SF₅, —SR⁸, aryl, and heteroaryl. In some embodiments is acompound of Formula (IIIb), or a pharmaceutically acceptable salt,solvate, or stereoisomer thereof, wherein m is 1 and R¹ is selected fromhalogen, C₁₋₆alkyl, C₁₋₆haloalkyl, C₃₋₈cycloalkyl, —NR⁵R⁶, and —OR⁷. Insome embodiments is a compound of Formula (IIIb), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein m is 1 and R¹is selected from halogen, C₁₋₆alkyl, C₁₋₆haloalkyl, C₃₋₈cycloalkyl, and—OR⁷. In some embodiments is a compound of Formula (IIIb), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein m is 1 and R¹ is halogen. In some embodiments is a compound ofFormula (IIIb), or a pharmaceutically acceptable salt, solvate, orstereoisomer thereof, wherein m is 1 and R¹ is F. In some embodiments isa compound of Formula (IIIb), or a pharmaceutically acceptable salt,solvate, or stereoisomer thereof, wherein m is 1 and R¹ is Cl. In someembodiments is a compound of Formula (IIIb), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein m is 1 and R¹is —CN. In some embodiments is a compound of Formula (IIIb), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein m is 1 and R¹ is C₁₋₆alkyl. In some embodiments is a compound ofFormula (IIIb), or a pharmaceutically acceptable salt, solvate, orstereoisomer thereof, wherein m is 1 and R¹ is —CH₃. In some embodimentsis a compound of Formula (IIIb), or a pharmaceutically acceptable salt,solvate, or stereoisomer thereof, wherein m is 1 and R¹ is —C≡CH. Insome embodiments is a compound of Formula (IIIb), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein m is 1 and R¹is C₁₋₆alkyl-OR⁷. In some embodiments is a compound of Formula (IIIb),or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein m is 1 and R¹ is —CH₂—O—CH₃. In some embodiments is a compoundof Formula (IIIb), or a pharmaceutically acceptable salt, solvate, orstereoisomer thereof, wherein m is 1 and R¹ is C₁₋₆haloalkyl. In someembodiments is a compound of Formula (IIIb), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein m is 1 and R¹is —CF₃. In some embodiments is a compound of Formula (IIIb), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein m is 1 and R¹ is C₃₋₈cycloalkyl. In some embodiments is acompound of Formula (IIIb), or a pharmaceutically acceptable salt,solvate, or stereoisomer thereof, wherein m is 1 and R¹ is —NR⁵R⁶. Insome embodiments is a compound of Formula (IIIb), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein m is 1, R¹ is—NR⁵R⁶, and R⁵ and R⁶, together with the nitrogen to which they areattached, form a heterocycloalkyl optionally substituted with one or twoR¹⁰. In some embodiments is a compound of Formula (IIIb), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein m is 1, R¹ is —NR⁵R⁶, and R⁵ and R⁶, together with the nitrogento which they are attached, form an unsubstituted heterocycloalkyl. Insome embodiments is a compound of Formula (IIIb), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein m is 1, R¹ is—NR⁵R⁶, and R⁵ and R⁶, together with the nitrogen to which they areattached, form a heterocycloalkyl substituted with one or two R¹⁰independently selected from C₁₋₆alkyl, C₃₋₈cycloalkyl, C₁₋₆haloalkyl,halogen, oxo, —C(O)NR⁸R⁹, —SO₂R⁸, —NR⁹C(O)R⁸, and —NR⁹SO₂R⁸. In someembodiments is a compound of Formula (IIIb), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein m is 1, R¹ is—NR⁵R⁶, and R⁵ and R⁶, together with the nitrogen to which they areattached, form a heterocycloalkyl substituted with one or two R¹⁰independently selected from C₁₋₆alkyl, C₃₋₈cycloalkyl, and —C(O)NR⁸R⁹.In some embodiments is a compound of Formula (IIIb), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein m is 1 and R¹ is —OR⁷. In some embodiments is a compound ofFormula (IIIb), or a pharmaceutically acceptable salt, solvate, orstereoisomer thereof, wherein m is 1, R¹ is —OR⁷, and R⁷ is selectedfrom C₁₋₆alkyl, C₁₋₆alkyl-O—C₁-6alkyl, C₁₋₆haloalkyl, C₃₋₈cycloalkyl,heterocycloalkyl, aryl, and heteroaryl. In some embodiments is acompound of Formula (IIIb), or a pharmaceutically acceptable salt,solvate, or stereoisomer thereof, wherein m is 1 and R¹ is —OCH₃. Insome embodiments is a compound of Formula (IIIb), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein m is 1 and R¹is —OCF₃. In some embodiments is a compound of Formula (IIIb), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein m is 1 and R¹ is —SO₂R¹². In some embodiments is a compound ofFormula (IIIb), or a pharmaceutically acceptable salt, solvate, orstereoisomer thereof, wherein m is 1 and R¹ is —SF₅. In some embodimentsis a compound of Formula (IIIb), or a pharmaceutically acceptable salt,solvate, or stereoisomer thereof, wherein m is 1 and R¹ is —SR⁸. In someembodiments is a compound of Formula (IIIb), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein m is 1 and R¹is aryl optionally substituted with one or two groups independentlyselected from halogen, C₁₋₆alkyl, C₁₋₆haloalkyl, and —C(O)NR⁸R⁹. In someembodiments is a compound of Formula (IIIb), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein m is 1 and R¹is heteroaryl optionally substituted with one or two groupsindependently selected from halogen, C₁₋₆alkyl, C₁₋₆haloalkyl, and—C(O)NR⁸R⁹. In some embodiments is a compound of Formula (IIIb), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein m is 1 and R¹ is selected from thiazole, pyrazine, pyrimidine,and pyridine, optionally substituted with one or two groupsindependently selected from halogen, C₁₋₆alkyl, C₁₋₆haloalkyl, and—C(O)NR⁸R⁹. In some embodiments is a compound of Formula (IIIb), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein m is 2. In some embodiments is a compound of Formula (IIIb), ora pharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein m is 2 and each R¹ is independently selected from halogen, —CN,C₁₋₆alkyl, C₂₋₆alkynyl, C₁₋₆alkyl-OR⁷, C₁₋₆haloalkyl, C₃₋₈cycloalkyl,—NR⁵R⁶, —OR⁷, —SO₂R¹², —SF₅, —SR⁸, aryl, and heteroaryl. In someembodiments is a compound of Formula (IIIb), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein m is 2 andeach R¹ is independently selected from halogen, C₁₋₆alkyl,C₁₋₆haloalkyl, C₃₋₈cycloalkyl, —NR⁵R⁶, and —OR⁷. In some embodiments isa compound of Formula (IIIb), or a pharmaceutically acceptable salt,solvate, or stereoisomer thereof, wherein m is 2 and each R¹ isindependently selected from halogen, —CN, C₁₋₆alkyl, C₁₋₆haloalkyl,—NR⁵R⁶, —OR⁷, and heteroaryl. In some embodiments is a compound ofFormula (IIIb), or a pharmaceutically acceptable salt, solvate, orstereoisomer thereof, wherein m is 2 and each R¹ is independentlyselected from halogen, C₁₋₆haloalkyl, —NR⁵R⁶, —OR⁷, thiazole, pyrazine,pyrimidine, and pyridine. In some embodiments is a compound of Formula(IIIb), or a pharmaceutically acceptable salt, solvate, or stereoisomerthereof, wherein m is 2 and each R¹ is independently selected fromhalogen, C₁₋₆alkyl, C₁₋₆haloalkyl, C₃₋₈cycloalkyl, and —OR⁷. In someembodiments is a compound of Formula (IIIb), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein m is 2, eachR¹ is independently selected from halogen, C₁₋₆alkyl, C₁₋₆haloalkyl,C₃₋₈cycloalkyl, and —OR⁷, and each R⁷ is independently selected fromC₁₋₆alkyl, C₁₋₆alkyl-O—C₁₋₆alkyl, C₁₋₆haloalkyl, C₃₋₈cycloalkyl,heterocycloalkyl, aryl, and heteroaryl. In some embodiments is acompound of Formula (IIIb), or a pharmaceutically acceptable salt,solvate, or stereoisomer thereof, wherein m is 2, each R¹ isindependently selected from halogen, C₁₋₆alkyl, C₁₋₆haloalkyl,C₃₋₈cycloalkyl, and —OR⁷, and each R⁷ is independently selected fromC₁₋₆alkyl, C₁₋₆haloalkyl, C₃₋₈cycloalkyl, and heterocycloalkyl. In someembodiments is a compound of Formula (IIIb), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein m is 3. Insome embodiments is a compound of Formula (IIIb), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein m is 3 andeach R¹ is independently selected from halogen, —CN, C₁₋₆alkyl,C₂₋₆alkynyl, C₁₋₆alkyl-OR⁷, C₁₋₆haloalkyl, C₃₋₈cycloalkyl, —NR⁵R⁶, —OR⁷,—SO₂R¹², —SF₅, —SR⁸, aryl, and heteroaryl. In some embodiments is acompound of Formula (IIIb), or a pharmaceutically acceptable salt,solvate, or stereoisomer thereof, wherein m is 3 and each R¹ isindependently selected from halogen, C₁₋₆alkyl, C₁₋₆haloalkyl,C₃₋₈cycloalkyl, —NR⁵R⁶, and —OR⁷. In some embodiments is a compound ofFormula (IIIb), or a pharmaceutically acceptable salt, solvate, orstereoisomer thereof, m is 3 and each R¹ is independently selected fromhalogen, C₁₋₆alkyl, C₁₋₆haloalkyl, C₃₋₈cycloalkyl, and —OR⁷. In someembodiments is a compound of Formula (IIIb), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein m is 3, eachR¹ is independently selected from halogen, C₁₋₆alkyl, C₁₋₆haloalkyl,C₃₋₈cycloalkyl, and —OR⁷, and each R⁷ is independently selected fromC₁₋₆alkyl, C₁₋₆alkyl-O—C₁₋₆alkyl, C₁₋₆haloalkyl, C₃₋₈cycloalkyl,heterocycloalkyl, aryl, and heteroaryl. In some embodiments is acompound of Formula (IIIb), or a pharmaceutically acceptable salt,solvate, or stereoisomer thereof, wherein m is 3, each R¹ isindependently selected from halogen, C₁₋₆alkyl, C₁₋₆haloalkyl,C₃₋₈cycloalkyl, and —OR⁷, and each R⁷ is independently selected fromC₁₋₆alkyl, 6haloalkyl, C₃₋₈cycloalkyl, and heterocycloalkyl.

In some embodiments is a compound of Formula (IIIb), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein n is 0. In some embodiments is a compound of Formula (IIIb), ora pharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein n is 1. In some embodiments is a compound of Formula (IIIb), ora pharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein n is 1 and R¹ is selected from halogen, —CN, C₁₋₆alkyl,6alkynyl, C₁₋₆alkyl-OR⁷, C₁₋₆haloalkyl, C₃₋₈cycloalkyl, —NR⁵R⁶, —OR⁷,—SO₂R¹², —SF₅, —SR⁸, aryl, and heteroaryl. In some embodiments is acompound of Formula (IIIb), or a pharmaceutically acceptable salt,solvate, or stereoisomer thereof, wherein n is 1 and R¹ is selected fromhalogen, C₁₋₆alkyl, C₁₋₆haloalkyl, C₃₋₈cycloalkyl, —NR⁵R⁶, and —OR⁷. Insome embodiments is a compound of Formula (IIIb), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein n is 1 and R¹is selected from halogen, C₁₋₆alkyl, C₁₋₆haloalkyl, C₃₋₈cycloalkyl, and—OR⁷. In some embodiments is a compound of Formula (IIIb), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein n is 1 and R¹ is halogen. In some embodiments is a compound ofFormula (IIIb), or a pharmaceutically acceptable salt, solvate, orstereoisomer thereof, wherein n is 1 and R¹ is F. In some embodiments isa compound of Formula (IIIb), or a pharmaceutically acceptable salt,solvate, or stereoisomer thereof, wherein n is 1 and R¹ is Cl. In someembodiments is a compound of Formula (IIIb), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein n is 1 and R¹is —CN. In some embodiments is a compound of Formula (IIIb), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein n is 1 and R¹ is C₁₋₆alkyl. In some embodiments is a compound ofFormula (IIIb), or a pharmaceutically acceptable salt, solvate, orstereoisomer thereof, wherein n is 1 and R¹ is —CH₃. In some embodimentsis a compound of Formula (IIIb), or a pharmaceutically acceptable salt,solvate, or stereoisomer thereof, wherein n is 1 and R¹ is —C≡CH. Insome embodiments is a compound of Formula (IIIb), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein n is 1 and R¹is C₁₋₆alkyl-OR⁷. In some embodiments is a compound of Formula (IIIb),or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein n is 1 and R¹ is —CH₂—O—CH₃. In some embodiments is a compoundof Formula (IIIb), or a pharmaceutically acceptable salt, solvate, orstereoisomer thereof, wherein n is 1 and R¹ is C₁₋₆haloalkyl. In someembodiments is a compound of Formula (IIIb), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein n is 1 and R¹is —CF₃. In some embodiments is a compound of Formula (IIIb), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein n is 1 and R¹ is C₃₋₈cycloalkyl. In some embodiments is acompound of Formula (IIIb), or a pharmaceutically acceptable salt,solvate, or stereoisomer thereof, wherein n is 1 and R¹ is —NR⁵R⁶. Insome embodiments is a compound of Formula (IIIb), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein n is 1, R¹ is—NR⁵R⁶, and R⁵ and R⁶, together with the nitrogen to which they areattached, form a heterocycloalkyl optionally substituted with one or twoR¹⁰. In some embodiments is a compound of Formula (IIIb), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein n is 1, R¹ is —NR⁵R⁶, and R⁵ and R⁶, together with the nitrogento which they are attached, form an unsubstituted heterocycloalkyl. Insome embodiments is a compound of Formula (IIIb), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein n is 1, R¹ is—NR⁵R⁶, and R⁵ and R⁶, together with the nitrogen to which they areattached, form a heterocycloalkyl substituted with one or two R¹⁰independently selected from C₁₋₆alkyl, C₃₋₈cycloalkyl, C₁₋₆haloalkyl,halogen, oxo, —C(O)NR⁸R⁹, —SO₂R⁸, —NR⁹C(O)R⁸, and —NR⁹SO₂R⁸. In someembodiments is a compound of Formula (IIIb), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein n is 1, R¹ is—NR⁵R⁶, and R⁵ and R⁶, together with the nitrogen to which they areattached, form a heterocycloalkyl substituted with one or two R¹⁰independently selected from C₁₋₆alkyl, C₃₋₈cycloalkyl, and —C(O)NR⁸R⁹.In some embodiments is a compound of Formula (IIIb), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein n is 1 and R¹ is —OR⁷. In some embodiments is a compound ofFormula (IIIb), or a pharmaceutically acceptable salt, solvate, orstereoisomer thereof, wherein n is 1, R¹ is —OR⁷, and R⁷ is selectedfrom C₁₋₆alkyl, C₁₋₆alkyl-O—C₁₋₆alkyl, C₁₋₆haloalkyl, C₃₋₈cycloalkyl,heterocycloalkyl, aryl, and heteroaryl. In some embodiments is acompound of Formula (IIIb), or a pharmaceutically acceptable salt,solvate, or stereoisomer thereof, wherein n is 1 and R¹ is —OCH₃. Insome embodiments is a compound of Formula (IIIb), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein n is 1 and R¹is —OCF₃. In some embodiments is a compound of Formula (IIIb), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein n is 1 and R¹ is —SO₂R¹². In some embodiments is a compound ofFormula (IIIb), or a pharmaceutically acceptable salt, solvate, orstereoisomer thereof, wherein n is 1 and R¹ is —SF₅. In some embodimentsis a compound of Formula (IIIb), or a pharmaceutically acceptable salt,solvate, or stereoisomer thereof, wherein n is 1 and R¹ is —SR⁸. In someembodiments is a compound of Formula (IIIb), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein n is 1 and R¹is aryl optionally substituted with one or two groups independentlyselected from halogen, C₁₋₆alkyl, C₁₋₆haloalkyl, and —C(O)NR⁸R⁹. In someembodiments is a compound of Formula (IIIb), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein n is 1 and R¹is heteroaryl optionally substituted with one or two groupsindependently selected from halogen, C₁₋₆alkyl, C₁₋₆haloalkyl, and—C(O)NR⁸R⁹. In some embodiments is a compound of Formula (IIIb), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein n is 1 and R¹ is selected from thiazole, pyrazine, pyrimidine,and pyridine, optionally substituted with one or two groupsindependently selected from halogen, C₁₋₆alkyl, C₁₋₆haloalkyl, and—C(O)NR⁸R⁹. In some embodiments is a compound of Formula (IIIb), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein n is 2. In some embodiments is a compound of Formula (IIIb), ora pharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein n is 2 and each R¹ is independently selected from halogen, —CN,C₁₋₆alkyl, C₂₋₆alkynyl, C₁₋₆alkyl-OR⁷, C₁₋₆haloalkyl, C₃₋₈cycloalkyl,—NR⁵R⁶, —OR⁷, —SO₂R¹², —SF₅, —SR⁸, aryl, and heteroaryl. In someembodiments is a compound of Formula (IIIb), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein n is 2 andeach R¹ is independently selected from halogen, C₁₋₆alkyl,C₁₋₆haloalkyl, C₃₋₈cycloalkyl, —NR⁵R⁶, and —OR⁷. In some embodiments isa compound of Formula (IIIb), or a pharmaceutically acceptable salt,solvate, or stereoisomer thereof, wherein n is 2 and each R¹ isindependently selected from halogen, —CN, C₁₋₆alkyl, C₁₋₆haloalkyl,—NR⁵R⁶, —OR⁷, and heteroaryl. In some embodiments is a compound ofFormula (IIIb), or a pharmaceutically acceptable salt, solvate, orstereoisomer thereof, wherein n is 2 and each R¹ is independentlyselected from halogen, C₁₋₆haloalkyl, —NR⁵R⁶, —OR⁷, thiazole, pyrazine,pyrimidine, and pyridine. In some embodiments is a compound of Formula(IIIb), or a pharmaceutically acceptable salt, solvate, or stereoisomerthereof, wherein n is 2 and each R¹ is independently selected fromhalogen, C₁₋₆alkyl, C₁₋₆haloalkyl, C₃₋₈cycloalkyl, and —OR⁷. In someembodiments is a compound of Formula (IIIb), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein n is 2, eachR¹ is independently selected from halogen, C₁₋₆alkyl, C₁₋₆haloalkyl,C₃₋₈cycloalkyl, and —OR⁷, and each R⁷ is independently selected fromC₁₋₆alkyl, C₁₋₆alkyl-O—C₁₋₆alkyl, C₁₋₆haloalkyl, C₃₋₈cycloalkyl,heterocycloalkyl, aryl, and heteroaryl. In some embodiments is acompound of Formula (IIIb), or a pharmaceutically acceptable salt,solvate, or stereoisomer thereof, wherein n is 2, each R¹ isindependently selected from halogen, C₁₋₆alkyl, C₁₋₆haloalkyl,C₃₋₈cycloalkyl, and —OR⁷, and each R⁷ is independently selected fromC₁₋₆alkyl, C₁₋₆haloalkyl, C₃₋₈cycloalkyl, and heterocycloalkyl. In someembodiments is a compound of Formula (IIIb), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein n is 3.

In some embodiments is a compound of Formula (IV):

wherein:

-   each R¹ is independently selected from halogen, —CN, C₁₋₆alkyl,    C₂₋₆alkynyl, C₁₋₆alkyl-OR⁷, C₁₋₆haloalkyl, C₃₋₈cycloalkyl, —NR⁵R⁶,    —C(O)NR⁵R⁶, —OR⁷, —SO₂R¹², —SF₅, —SR⁸, aryl, and heteroaryl, wherein    aryl and heteroaryl are optionally substituted with one or two    groups independently selected from halogen, C₁₋₆alkyl,    C₁₋₆haloalkyl, and —C(O)NR⁸R⁹; or two adjacent R¹ form a    heterocycloalkyl ring optionally substituted with one or two R¹¹;-   R³ is selected from halogen, —CN, C₁₋₆alkyl, C₁₋₆haloalkyl, —NR⁸R⁹,    —C(O)NR⁸R⁹, —NR⁸C(O)R⁹, and —NR⁹SO₂R⁸;-   R^(3a) is selected from halogen, C₁₋₆alkyl, and C₁₋₆haloalkyl;-   each R⁵ and R⁶ is independently selected from H, C₁₋₆alkyl, and    C₃₋₈cycloalkyl; or R⁵ and R⁶, together with the nitrogen to which    they are attached, form a heterocycloalkyl optionally substituted    with one or two R¹⁰;-   each R⁷ is independently selected from H, C₁₋₆alkyl,    C₁₋₆alkyl-O—C₁₋₆alkyl, C₁₋₆haloalkyl, C₃₋₈cycloalkyl,    heterocycloalkyl, aryl, and heteroaryl, wherein heterocycloalkyl,    aryl, and heteroaryl are optionally substituted with one or two    groups independently selected from halogen, C₁₋₆alkyl, and    C₁₋₆haloalkyl;    -   each R⁸ and R⁹ is independently selected from H, C₁₋₆alkyl,        C₃₋₈cycloalkyl, aryl, and heteroaryl;-   each R¹⁰ is independently selected from C₁₋₆alkyl, C₃₋₈cycloalkyl,    C₁₋₆haloalkyl, halogen, oxo, —CN, —C(O)OR⁸, —C(O)R⁸, —C(O)NR⁸R⁹,    —SO₂R⁸, —NR⁹C(O)R⁸, and —NR⁹SO₂R⁸;-   each R¹¹ is independently selected from halogen and C₁₋₆alkyl;-   each R¹² is independently selected from C₁₋₆alkyl and    C₃₋₈cycloalkyl;-   m is 0, 1, 2, 3, 4, or 5; and-   q is 0 or 1;    or a pharmaceutically acceptable salt, solvate, or stereoisomer    thereof.

In some embodiments is a compound of Formula (IV), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein R³ ishalogen. In some embodiments is a compound of Formula (IV), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein R³ is —CN. In some embodiments is a compound of Formula (IV), ora pharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein R³ is C₁₋₆alkyl. In some embodiments is a compound of Formula(IV), or a pharmaceutically acceptable salt, solvate, or stereoisomerthereof, wherein R³ is —CH₃. In some embodiments is a compound ofFormula (IV), or a pharmaceutically acceptable salt, solvate, orstereoisomer thereof, wherein R³ is C₁₋₆haloalkyl. In some embodimentsis a compound of Formula (IV), or a pharmaceutically acceptable salt,solvate, or stereoisomer thereof, wherein R³ is —CF₃. In someembodiments is a compound of Formula (IV), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein R³ is —NR⁸R⁹.In some embodiments is a compound of Formula (IV), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein R³ is —NH₂.In some embodiments is a compound of Formula (IV), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein R³ is—C(O)NR⁸R⁹. In some embodiments is a compound of Formula (IV), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein R³ is —C(O)NH₂. In some embodiments is a compound of Formula(IV), or a pharmaceutically acceptable salt, solvate, or stereoisomerthereof, wherein R³ is —NR⁸C(O)R⁹. In some embodiments is a compound ofFormula (IV), or a pharmaceutically acceptable salt, solvate, orstereoisomer thereof, wherein R³ is —NHC(O)CH₃. In some embodiments is acompound of Formula (IV), or a pharmaceutically acceptable salt,solvate, or stereoisomer thereof, wherein q is 0. In some embodiments isa compound of Formula (IV), or a pharmaceutically acceptable salt,solvate, or stereoisomer thereof, wherein q is 1. In some embodiments isa compound of Formula (IV), or a pharmaceutically acceptable salt,solvate, or stereoisomer thereof, wherein q is 1 and R^(3a) is halogen.In some embodiments is a compound of Formula (IV), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein q is 1 andR^(3a) is C₁₋₆alkyl. In some embodiments is a compound of Formula (IV),or a pharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein q is 1 and R^(3a) is C₁₋₆haloalkyl.

In some embodiments is a compound of Formula (IV), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein m is 0. Insome embodiments is a compound of Formula (IV), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein m is 1. Insome embodiments is a compound of Formula (IV), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein m is 1 and R¹is selected from halogen, —CN, C₁₋₆alkyl, C₂₋₆alkynyl, C₁₋₆alkyl-OR⁷,C₁₋₆haloalkyl, C₃₋₈cycloalkyl, —NR⁵R⁶, —OR⁷, —SO₂R¹², —SF₅, —SR⁸, aryl,and heteroaryl. In some embodiments is a compound of Formula (IV), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein m is 1 and R¹ is selected from halogen, C₁₋₆alkyl,C₁₋₆haloalkyl, C₃₋₈cycloalkyl, —NR⁵R⁶, and —OR⁷. In some embodiments isa compound of Formula (IV), or a pharmaceutically acceptable salt,solvate, or stereoisomer thereof, wherein m is 1 and R¹ is selected fromhalogen, C₁₋₆alkyl, C₁₋₆haloalkyl, C₃₋₈cycloalkyl, and —OR⁷. In someembodiments is a compound of Formula (IV), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein m is 1 and R¹is halogen. In some embodiments is a compound of Formula (IV), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein m is 1 and R¹ is F. In some embodiments is a compound of Formula(IV), or a pharmaceutically acceptable salt, solvate, or stereoisomerthereof, wherein m is 1 and R¹ is Cl. In some embodiments is a compoundof Formula (IV), or a pharmaceutically acceptable salt, solvate, orstereoisomer thereof, wherein m is 1 and R¹ is —CN. In some embodimentsis a compound of Formula (IV), or a pharmaceutically acceptable salt,solvate, or stereoisomer thereof, wherein m is 1 and R¹ is C₁₋₆alkyl. Insome embodiments is a compound of Formula (IV), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein m is 1 and R¹is —CH₃. In some embodiments is a compound of Formula (IV), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein m is 1 and R¹ is —C≡CH In some embodiments is a compound ofFormula (IV), or a pharmaceutically acceptable salt, solvate, orstereoisomer thereof, wherein m is 1 and R¹ is C₁₋₆alkyl-OR⁷. In someembodiments is a compound of Formula (IV), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein m is 1 and R¹is —CH₂—O—CH₃. In some embodiments is a compound of Formula (IV), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein m is 1 and R¹ is C₁₋₆haloalkyl. In some embodiments is acompound of Formula (IV), or a pharmaceutically acceptable salt,solvate, or stereoisomer thereof, wherein m is 1 and R¹ is —CF₃. In someembodiments is a compound of Formula (IV), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein m is 1 and R¹is C₃₋₈cycloalkyl. In some embodiments is a compound of Formula (IV), ora pharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein m is 1 and R¹ is —NR⁵R⁶. In some embodiments is a compound ofFormula (IV), or a pharmaceutically acceptable salt, solvate, orstereoisomer thereof, wherein m is 1, R¹ is —NR⁵R⁶, and R⁵ and R⁶,together with the nitrogen to which they are attached, form aheterocycloalkyl optionally substituted with one or two R¹⁰. In someembodiments is a compound of Formula (IV), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein m is 1, R¹ is—NR⁵R⁶, and R⁵ and R⁶, together with the nitrogen to which they areattached, form an unsubstituted heterocycloalkyl. In some embodiments isa compound of Formula (IV), or a pharmaceutically acceptable salt,solvate, or stereoisomer thereof, wherein m is 1, R¹ is —NR⁵R⁶, and R⁵and R⁶, together with the nitrogen to which they are attached, form aheterocycloalkyl substituted with one or two R¹⁰ independently selectedfrom C₁₋₆alkyl, C₃₋₈cycloalkyl, C₁₋₆haloalkyl, halogen, oxo, —C(O)NR⁸R⁹,—SO₂R⁸, —NR⁹C(O)R⁸, and —NR⁹SO₂R⁸. In some embodiments is a compound ofFormula (IV), or a pharmaceutically acceptable salt, solvate, orstereoisomer thereof, wherein m is 1, R¹ is —NR⁵R⁶, and R⁵ and R⁶,together with the nitrogen to which they are attached, form aheterocycloalkyl substituted with one or two R¹⁰ independently selectedfrom C₁₋₆alkyl, C₃₋₈cycloalkyl, and —C(O)NR⁸R⁹. In some embodiments is acompound of Formula (IV), or a pharmaceutically acceptable salt,solvate, or stereoisomer thereof, wherein m is 1 and R¹ is —OR⁷. In someembodiments is a compound of Formula (IV), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein m is 1, le is—OR⁷, and R⁷ is selected from C₁₋₆alkyl, C₁₋₆alkyl-O—C₁₋₆alkyl,C₁₋₆haloalkyl, C₃₋₈cycloalkyl, heterocycloalkyl, aryl, and heteroaryl.In some embodiments is a compound of Formula (IV), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein m is 1 and R¹is —OCH₃. In some embodiments is a compound of Formula (IV), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein m is 1 and R¹ is —OCF₃. In some embodiments is a compound ofFormula (IV), or a pharmaceutically acceptable salt, solvate, orstereoisomer thereof, wherein m is 1 and R¹ is —SO₂R¹². In someembodiments is a compound of Formula (IV), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein m is 1 and R¹is —SF₅. In some embodiments is a compound of Formula (IV), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein m is 1 and R¹ is —SR⁸. In some embodiments is a compound ofFormula (IV), or a pharmaceutically acceptable salt, solvate, orstereoisomer thereof, wherein m is 1 and R¹ is aryl optionallysubstituted with one or two groups independently selected from halogen,C₁₋₆alkyl, C₁₋₆haloalkyl, and —C(O)NR⁸R⁹. In some embodiments is acompound of Formula (IV), or a pharmaceutically acceptable salt,solvate, or stereoisomer thereof, wherein m is 1 and R¹ is heteroaryloptionally substituted with one or two groups independently selectedfrom halogen, C₁₋₆alkyl, C₁₋₆haloalkyl, and —C(O)NR⁸R⁹. In someembodiments is a compound of Formula (IV), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein m is 1 and R¹is selected from thiazole, pyrazine, pyrimidine, and pyridine,optionally substituted with one or two groups independently selectedfrom halogen, C₁₋₆alkyl, C₁₋₆haloalkyl, and —C(O)NR⁸R⁹. In someembodiments is a compound of Formula (IV), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein m is 2. Insome embodiments is a compound of Formula (IV), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein m is 2 andeach R¹ is independently selected from halogen, —CN, C₁₋₆alkyl,C₂₋₆alkynyl, C₁₋₆alkyl-OR⁷, C₁₋₆haloalkyl, C₃₋₈cycloalkyl, —NR⁵R⁶, —OR⁷,—SO₂R¹², —SF₅, —SR⁸, aryl, and heteroaryl. In some embodiments is acompound of Formula (IV), or a pharmaceutically acceptable salt,solvate, or stereoisomer thereof, wherein m is 2 and each R¹ isindependently selected from halogen, C₁₋₆alkyl, C₁₋₆haloalkyl,C₃₋₈cycloalkyl, —NR⁵R⁶, and —OR⁷. In some embodiments is a compound ofFormula (IV), or a pharmaceutically acceptable salt, solvate, orstereoisomer thereof, wherein m is 2 and each R¹ is independentlyselected from halogen, —CN, C₁₋₆alkyl, C₁₋₆haloalkyl, —NR⁵R⁶, —OR⁷, andheteroaryl. In some embodiments is a compound of Formula (IV), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein m is 2 and each R¹ is independently selected from halogen,C₁₋₆haloalkyl, —NR⁵R⁶, —OR⁷, thiazole, pyrazine, pyrimidine, andpyridine. In some embodiments is a compound of Formula (IV), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein m is 2 and each R¹ is independently selected from halogen,C₁₋₆alkyl, C₁₋₆haloalkyl, C₃₋₈cycloalkyl, and —OR⁷. In some embodimentsis a compound of Formula (IV), or a pharmaceutically acceptable salt,solvate, or stereoisomer thereof, wherein m is 2, each R¹ isindependently selected from halogen, C₁₋₆alkyl, C₁₋₆haloalkyl,C₃₋₈cycloalkyl, and —OR⁷, and each R⁷ is independently selected fromC₁₋₆alkyl, C₁₋₆alkyl-O—C₁₋₆alkyl, C₁₋₆haloalkyl, C₃₋₈cycloalkyl,heterocycloalkyl, aryl, and heteroaryl. In some embodiments is acompound of Formula (IV), or a pharmaceutically acceptable salt,solvate, or stereoisomer thereof, wherein m is 2, each R¹ isindependently selected from halogen, C₁₋₆alkyl, C₁₋₆haloalkyl,C₃₋₈cycloalkyl, and —OR⁷, and each R⁷ is independently selected fromC₁₋₆alkyl, C₁₋₆haloalkyl, C₃₋₈cycloalkyl, and heterocycloalkyl. In someembodiments is a compound of Formula (IV), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein m is 3. Insome embodiments is a compound of Formula (IV), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein m is 3 andeach R¹ is independently selected from halogen, —CN, C₁₋₆alkyl,C₂₋₆alkynyl, C₁₋₆alkyl-OR⁷, C₁₋₆haloalkyl, C₃₋₈cycloalkyl, —NR⁵R⁶, —OR⁷,—SO₂R¹², —SF₅, —SR⁸, aryl, and heteroaryl. In some embodiments is acompound of Formula (IV), or a pharmaceutically acceptable salt,solvate, or stereoisomer thereof, wherein m is 3 and each R¹ isindependently selected from halogen, C₁₋₆alkyl, C₁₋₆haloalkyl,C₃₋₈cycloalkyl, —NR⁵R⁶, and —OR⁷. In some embodiments is a compound ofFormula (IV), or a pharmaceutically acceptable salt, solvate, orstereoisomer thereof, m is 3 and each R¹ is independently selected fromhalogen, C₁₋₆alkyl, C₁₋₆haloalkyl, C₃₋₈cycloalkyl, and —OR⁷. In someembodiments is a compound of Formula (IV), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein m is 3, eachR¹ is independently selected from halogen, C₁₋₆alkyl, C₁₋₆haloalkyl,C₃₋₈cycloalkyl, and —OR⁷, and each R⁷ is independently selected fromC₁₋₆alkyl, C₁₋₆alkyl-O—C₁₋₆alkyl, C₁₋₆haloalkyl, C₃₋₈cycloalkyl,heterocycloalkyl, aryl, and heteroaryl. In some embodiments is acompound of Formula (IV), or a pharmaceutically acceptable salt,solvate, or stereoisomer thereof, wherein m is 3, each R¹ isindependently selected from halogen, C₁₋₆alkyl, C₁₋₆haloalkyl,C₃₋₈cycloalkyl, and —OR⁷, and each R⁷ is independently selected fromC₁₋₆alkyl, C₁₋₆haloalkyl, C₃₋₈cycloalkyl, and heterocycloalkyl.

In some embodiments is a compound of Formula (IV), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein n is 0. Insome embodiments is a compound of Formula (IV), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein n is 1. Insome embodiments is a compound of Formula (IV), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein n is 1 and R¹is selected from halogen, —CN, C₁₋₆alkyl, C₂₋₆alkynyl, C₁₋₆alkyl-OR⁷,C₁₋₆haloalkyl, C₃₋₈cycloalkyl, —NR⁵R⁶, —OR⁷, —SO₂R¹², —SF₅, —SR⁸, aryl,and heteroaryl. In some embodiments is a compound of Formula (IV), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein n is 1 and R¹ is selected from halogen, C₁₋₆alkyl,C₁₋₆haloalkyl, C₃₋₈cycloalkyl, —NR⁵R⁶, and —OR⁷. In some embodiments isa compound of Formula (IV), or a pharmaceutically acceptable salt,solvate, or stereoisomer thereof, wherein n is 1 and R¹ is selected fromhalogen, C₁₋₆alkyl, C₁₋₆haloalkyl, C₃₋₈cycloalkyl, and —OR⁷. In someembodiments is a compound of Formula (IV), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein n is 1 and R¹is halogen. In some embodiments is a compound of Formula (IV), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein n is 1 and R¹ is F. In some embodiments is a compound of Formula(IV), or a pharmaceutically acceptable salt, solvate, or stereoisomerthereof, wherein n is 1 and R¹ is Cl. In some embodiments is a compoundof Formula (IV), or a pharmaceutically acceptable salt, solvate, orstereoisomer thereof, wherein n is 1 and R¹ is —CN. In some embodimentsis a compound of Formula (IV), or a pharmaceutically acceptable salt,solvate, or stereoisomer thereof, wherein n is 1 and R¹ is C₁₋₆alkyl. Insome embodiments is a compound of Formula (IV), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein n is 1 and R¹is —CH₃. In some embodiments is a compound of Formula (IV), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein n is 1 and R¹ is —C≡CH In some embodiments is a compound ofFormula (IV), or a pharmaceutically acceptable salt, solvate, orstereoisomer thereof, wherein n is 1 and R¹ is C₁₋₆alkyl-OR⁷. In someembodiments is a compound of Formula (IV), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein n is 1 and R¹is —CH₂—O—CH₃. In some embodiments is a compound of Formula (IV), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein n is 1 and R¹ is C₁₋₆haloalkyl. In some embodiments is acompound of Formula (IV), or a pharmaceutically acceptable salt,solvate, or stereoisomer thereof, wherein n is 1 and R¹ is —CF₃. In someembodiments is a compound of Formula (IV), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein n is 1 and R¹is C₃₋₈cycloalkyl. In some embodiments is a compound of Formula (IV), ora pharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein n is 1 and R¹ is —NR⁵R⁶. In some embodiments is a compound ofFormula (IV), or a pharmaceutically acceptable salt, solvate, orstereoisomer thereof, wherein n is 1, R¹ is —NR⁵R⁶, and R⁵ and R⁶,together with the nitrogen to which they are attached, form aheterocycloalkyl optionally substituted with one or two R¹⁰. In someembodiments is a compound of Formula (IV), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein n is 1, R¹ is—NR⁵R⁶, and R⁵ and R⁶, together with the nitrogen to which they areattached, form an unsubstituted heterocycloalkyl. In some embodiments isa compound of Formula (IV), or a pharmaceutically acceptable salt,solvate, or stereoisomer thereof, wherein n is 1, R¹ is —NR⁵R⁶, and R⁵and R⁶, together with the nitrogen to which they are attached, form aheterocycloalkyl substituted with one or two R¹⁰ independently selectedfrom C₁₋₆alkyl, C₃₋₈cycloalkyl, C₁₋₆haloalkyl, halogen, oxo, —C(O)NR⁸R⁹,—SO₂R⁸, —NR⁹C(O)R⁸, and —NR⁹SO₂R⁸. In some embodiments is a compound ofFormula (IV), or a pharmaceutically acceptable salt, solvate, orstereoisomer thereof, wherein n is 1, R¹ is —NR⁵R⁶, and R⁵ and R⁶,together with the nitrogen to which they are attached, form aheterocycloalkyl substituted with one or two R¹⁰ independently selectedfrom C₁₋₆alkyl, C₃₋₈cycloalkyl, and —C(O)NR⁸R⁹. In some embodiments is acompound of Formula (IV), or a pharmaceutically acceptable salt,solvate, or stereoisomer thereof, wherein n is 1 and R¹ is —OR⁷. In someembodiments is a compound of Formula (IV), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein n is 1, le is—OR⁷, and R⁷ is selected from C₁₋₆alkyl, C₁₋₆alkyl-O—C₁₋₆alkyl,C₁₋₆haloalkyl, C₃₋₈cycloalkyl, heterocycloalkyl, aryl, and heteroaryl.In some embodiments is a compound of Formula (IV), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein n is 1 and R¹is —OCH₃. In some embodiments is a compound of Formula (IV), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein n is 1 and R¹ is —OCF₃. In some embodiments is a compound ofFormula (IV), or a pharmaceutically acceptable salt, solvate, orstereoisomer thereof, wherein n is 1 and R¹ is —SO₂R¹². In someembodiments is a compound of Formula (IV), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein n is 1 and R¹is —SF₅. In some embodiments is a compound of Formula (IV), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein n is 1 and R¹ is —SR⁸. In some embodiments is a compound ofFormula (IV), or a pharmaceutically acceptable salt, solvate, orstereoisomer thereof, wherein n is 1 and R¹ is aryl optionallysubstituted with one or two groups independently selected from halogen,C₁₋₆alkyl, C₁₋₆haloalkyl, and —C(O)NR⁸R⁹. In some embodiments is acompound of Formula (IV), or a pharmaceutically acceptable salt,solvate, or stereoisomer thereof, wherein n is 1 and R¹ is heteroaryloptionally substituted with one or two groups independently selectedfrom halogen, C₁₋₆alkyl, C₁₋₆haloalkyl, and —C(O)NR⁸R⁹. In someembodiments is a compound of Formula (IV), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein n is 1 and R¹is selected from thiazole, pyrazine, pyrimidine, and pyridine,optionally substituted with one or two groups independently selectedfrom halogen, C₁₋₆alkyl, C₁₋₆haloalkyl, and —C(O)NR⁸R⁹. In someembodiments is a compound of Formula (IV), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein n is 2. Insome embodiments is a compound of Formula (IV), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein n is 2 andeach R¹ is independently selected from halogen, —CN, C₁₋₆alkyl,C₂₋₆alkynyl, C₁₋₆alkyl-OR⁷, C₁₋₆haloalkyl, C₃₋₈cycloalkyl, —NR⁵R⁶,—SO₂R¹², —SF₅, —SR⁸, aryl, and heteroaryl. In some embodiments is acompound of Formula (IV), or a pharmaceutically acceptable salt,solvate, or stereoisomer thereof, wherein n is 2 and each R¹ isindependently selected from halogen, C₁₋₆alkyl, C₁₋₆haloalkyl,C₃₋₈cycloalkyl, —NR⁵R⁶, and —OR⁷. In some embodiments is a compound ofFormula (IV), or a pharmaceutically acceptable salt, solvate, orstereoisomer thereof, wherein n is 2 and each R¹ is independentlyselected from halogen, —CN, C₁₋₆alkyl, C₁₋₆haloalkyl, —NR⁵R⁶, —OR⁷, andheteroaryl. In some embodiments is a compound of Formula (IV), or apharmaceutically acceptable salt, solvate, or stereoisomer thereof,wherein n is 2 and each R¹ is independently selected from halogen,C₁₋₆haloalkyl, —NR⁵R⁶, thiazole, pyrazine, pyrimidine, and pyridine. Insome embodiments is a compound of Formula (IV), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein n is 2 andeach R¹ is independently selected from halogen, C₁₋₆alkyl,C₁₋₆haloalkyl, C₃₋₈cycloalkyl, and —OR⁷. In some embodiments is acompound of Formula (IV), or a pharmaceutically acceptable salt,solvate, or stereoisomer thereof, wherein n is 2, each R¹ isindependently selected from halogen, C₁₋₆alkyl, C₁₋₆haloalkyl,C₃₋₈cycloalkyl, and —OR⁷, and each R⁷ is independently selected fromC₁₋₆alkyl, C₁₋₆alkyl-O—C₁₋₆alkyl, C₁₋₆haloalkyl, C₃₋₈cycloalkyl,heterocycloalkyl, aryl, and heteroaryl. In some embodiments is acompound of Formula (IV), or a pharmaceutically acceptable salt,solvate, or stereoisomer thereof, wherein n is 2, each R¹ isindependently selected from halogen, C₁₋₆alkyl, C₁₋₆haloalkyl,C₃₋₈cycloalkyl, and —OR⁷, and each R⁷ is independently selected fromC₁₋₆alkyl, C₁₋₆haloalkyl, C₃₋₈cycloalkyl, and heterocycloalkyl. In someembodiments is a compound of Formula (IV), or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, wherein n is 3.

Further embodiments provided herein include combinations of one or moreof the particular embodiments set forth above.

In some embodiments, the compound disclosed herein is a compound of anyone of Examples 1-86, or a pharmaceutically acceptable salt, solvate, orstereoisomer thereof.

Preparation of the Compounds

The compounds used in the reactions described herein are made accordingto known organic synthesis techniques, starting from commerciallyavailable chemicals and/or from compounds described in the chemicalliterature. “Commercially available chemicals” are obtained fromstandard commercial sources including Acros Organics (Geel, Belgium),Aldrich Chemical (Milwaukee, Wis., including Sigma Chemical and Fluka),Apin Chemicals Ltd. (Milton Park, UK), Ark Pharm, Inc. (Libertyville,Ill.), Avocado Research (Lancashire, U.K.), BDH Inc. (Toronto, Canada),Bionet (Cornwall, U.K.), Chemservice Inc. (West Chester, Pa.),Combi-blocks (San Diego, Calif.), Crescent Chemical Co. (Hauppauge,N.Y.), eMolecules (San Diego, Calif.), Fisher Scientific Co.(Pittsburgh, Pa.), Fisons Chemicals (Leicestershire, UK), FrontierScientific (Logan, Utah), ICN Biomedicals, Inc. (Costa Mesa, Calif.),Key Organics (Cornwall, U.K.), Lancaster Synthesis (Windham, N.H.),Matrix Scientific, (Columbia, S.C.), Maybridge Chemical Co. Ltd.(Cornwall, U.K.), Parish Chemical Co. (Orem, Utah), Pfaltz & Bauer, Inc.(Waterbury, Conn.), Polyorganix (Houston, Tex.), Pierce Chemical Co.(Rockford, Ill.), Riedel de Haen AG (Hanover, Germany), Ryan Scientific,Inc. (Mount Pleasant, S.C.), Spectrum Chemicals (Gardena, Calif.),Sundia Meditech, (Shanghai, China), TCI America (Portland, Oreg.), TransWorld Chemicals, Inc. (Rockville, Md.), and WuXi (Shanghai, China).

Suitable reference books and treatises that detail the synthesis ofreactants useful in the preparation of compounds described herein, orprovide references to articles that describe the preparation, includefor example, “Synthetic Organic Chemistry”, John Wiley & Sons, Inc., NewYork; S. R. Sandler et al., “Organic Functional Group Preparations,” 2ndEd., Academic Press, New York, 1983; H. O. House, “Modern SyntheticReactions”, 2nd Ed., W. A. Benjamin, Inc. Menlo Park, Calif. 1972; T. L.Gilchrist, “Heterocyclic Chemistry”, 2nd Ed., John Wiley & Sons, NewYork, 1992; J. March, “Advanced Organic Chemistry: Reactions, Mechanismsand Structure”, 4th Ed., Wiley-Interscience, New York, 1992. Additionalsuitable reference books and treatises that detail the synthesis ofreactants useful in the preparation of compounds described herein, orprovide references to articles that describe the preparation, includefor example, Fuhrhop, J. and Penzlin G. “Organic Synthesis: Concepts,Methods, Starting Materials”, Second, Revised and Enlarged Edition(1994) John Wiley & Sons ISBN: 3-527-29074-5; Hoffman, R. V. “OrganicChemistry, An Intermediate Text” (1996) Oxford University Press, ISBN0-19-509618-5; Larock, R. C. “Comprehensive Organic Transformations: AGuide to Functional Group Preparations” 2nd Edition (1999) Wiley-VCH,ISBN: 0-471-19031-4; March, J. “Advanced Organic Chemistry: Reactions,Mechanisms, and Structure” 4th Edition (1992) John Wiley & Sons, ISBN:0-471-60180-2; Otera, J. (editor) “Modern Carbonyl Chemistry” (2000)Wiley-VCH, ISBN: 3-527-29871-1; Patai, S. “Patai's 1992 Guide to theChemistry of Functional Groups” (1992) Interscience ISBN: 0-471-93022-9;Solomons, T. W. G. “Organic Chemistry” 7th Edition (2000) John Wiley &Sons, ISBN: 0-471-19095-0; Stowell, J. C., “Intermediate OrganicChemistry” 2nd Edition (1993) Wiley-Interscience, ISBN: 0-471-57456-2;“Industrial Organic Chemicals: Starting Materials and Intermediates: AnUllmann's Encyclopedia” (1999) John Wiley & Sons, ISBN: 3-527-29645-X,in 8 volumes; “Organic Reactions” (1942-2000) John Wiley & Sons, in over55 volumes; and “Chemistry of Functional Groups” John Wiley & Sons, in73 volumes.

Specific and analogous reactants are also identified through the indicesof known chemicals prepared by the Chemical Abstract Service of theAmerican Chemical Society, which are available in most public anduniversity libraries, as well as through on-line databases (the AmericanChemical Society, Washington, D.C., may be contacted for more details).Chemicals that are known but not commercially available in catalogs areoptionally prepared by custom chemical synthesis houses, where many ofthe standard chemical supply houses (e.g., those listed above) providecustom synthesis services. A reference for the preparation and selectionof pharmaceutical salts of the compounds described herein is P. H. Stahl& C. G. Wermuth “Handbook of Pharmaceutical Salts”, Verlag HelveticaChimica Acta, Zurich, 2002.

Further Forms of Compounds Disclosed Herein Isomers

Furthermore, in some embodiments, the compounds described herein existas geometric isomers. In some embodiments, the compounds describedherein possess one or more double bonds. The compounds presented hereininclude all cis, trans, syn, anti, entgegen (F), and zusammen (Z)isomers as well as the corresponding mixtures thereof. In somesituations, compounds exist as tautomers. The compounds described hereininclude all possible tautomers within the formulas described herein. Insome situations, the compounds described herein possess one or morechiral centers and each center exists in the R configuration or Sconfiguration. The compounds described herein include alldiastereomeric, enantiomeric, and epimeric forms as well as thecorresponding mixtures thereof. In additional embodiments of thecompounds and methods provided herein, mixtures of enantiomers and/ordiastereoisomers, resulting from a single preparative step, combination,or interconversion, are useful for the applications described herein. Insome embodiments, the compounds described herein are prepared asoptically pure enantiomers by chiral chromatographic resolution of theracemic mixture. In some embodiments, the compounds described herein areprepared as their individual stereoisomers by reacting a racemic mixtureof the compound with an optically active resolving agent to form a pairof diastereoisomeric compounds, separating the diastereomers andrecovering the optically pure enantiomers. In some embodiments,dissociable complexes are preferred (e.g., crystalline diastereomericsalts). In some embodiments, the diastereomers have distinct physicalproperties (e.g., melting points, boiling points, solubilities,reactivity, etc.) and are separated by taking advantage of thesedissimilarities. In some embodiments, the diastereomers are separated bychiral chromatography, or preferably, by separation/resolutiontechniques based upon differences in solubility. In some embodiments,the optically pure enantiomer is then recovered, along with theresolving agent, by any practical means that does not result inracemization.

Labeled Compounds

In some embodiments, the compounds described herein exist in theirisotopically-labeled forms. In some embodiments, the methods disclosedherein include methods of treating diseases by administering suchisotopically-labeled compounds. In some embodiments, the methodsdisclosed herein include methods of treating diseases by administeringsuch isotopically-labeled compounds as pharmaceutical compositions.Thus, in some embodiments, the compounds disclosed herein includeisotopically-labeled compounds, which are identical to those recitedherein, but for the fact that one or more atoms are replaced by an atomhaving an atomic mass or mass number different from the atomic mass ormass number usually found in nature. Examples of isotopes that areincorporated into compounds described herein include isotopes ofhydrogen, carbon, nitrogen, oxygen, phosphorous, sulfur, fluorine andchloride, such as ²H, ³H, ¹³C, ¹⁴C, ¹⁵N, ¹⁸O, ¹⁷O, ³¹P, ³²P, ³⁵S, ¹⁸F,and ³⁶Cl, respectively. Compounds described herein, and thepharmaceutically acceptable salts, esters, solvate, hydrates, orderivatives thereof which contain the aforementioned isotopes and/orother isotopes of other atoms are within the scope of this invention.Certain isotopically-labeled compounds, for example those into whichradioactive isotopes such as ³H and ¹⁴C are incorporated, are useful indrug and/or substrate tissue distribution assays. Tritiated, i. e., ³Hand carbon-14, i. e., ¹⁴C, isotopes are particularly preferred for theirease of preparation and detectability. Further, substitution with heavyisotopes such as deuterium, i.e., ²H, produces certain therapeuticadvantages resulting from greater metabolic stability, for exampleincreased in vivo half-life or reduced dosage requirements. In someembodiments, the isotopically labeled compounds, pharmaceuticallyacceptable salt, ester, solvate, hydrate, or derivative thereof isprepared by any suitable method.

In some embodiments, the compounds described herein are labeled by othermeans, including, but not limited to, the use of chromophores orfluorescent moieties, bioluminescent labels, or chemiluminescent labels.

Pharmaceutically Acceptable Salts

In some embodiments, the compounds described herein exist as theirpharmaceutically acceptable salts. In some embodiments, the methodsdisclosed herein include methods of treating diseases by administeringsuch pharmaceutically acceptable salts. In some embodiments, the methodsdisclosed herein include methods of treating diseases by administeringsuch pharmaceutically acceptable salts as pharmaceutical compositions.

In some embodiments, the compounds described herein possess acidic orbasic groups and therefore react with any of a number of inorganic ororganic bases, and inorganic and organic acids, to form apharmaceutically acceptable salt. In some embodiments, these salts areprepared in situ during the final isolation and purification of thecompounds described herein, or by separately reacting a purifiedcompound in its free form with a suitable acid or base, and isolatingthe salt thus formed.

Solvates

In some embodiments, the compounds described herein exist as solvates.In some embodiments, are methods of treating diseases by administeringsuch solvates. Further described herein are methods of treating diseasesby administering such solvates as pharmaceutical compositions.

Solvates contain either stoichiometric or non-stoichiometric amounts ofa solvent, and, in some embodiments, are formed during the process ofcrystallization with pharmaceutically acceptable solvents such as water,ethanol, and the like. Hydrates are formed when the solvent is water, oralcoholates are formed when the solvent is alcohol. Solvates of thecompounds described herein are conveniently prepared or formed duringthe processes described herein. By way of example only, hydrates of thecompounds described herein are conveniently prepared byrecrystallization from an aqueous/organic solvent mixture, using organicsolvents including, but not limited to, dioxane, tetrahydrofuran, ormethanol. In addition, the compounds provided herein exist in unsolvatedas well as solvated forms. In general, the solvated forms are consideredequivalent to the unsolvated forms for the purposes of the compounds andmethods provided herein.

Prodrugs

In some embodiments, the compounds described herein exist in prodrugform. Further described herein are methods of treating diseases byadministering such prodrugs. Also described herein are methods oftreating diseases by administering such prodrugs as pharmaceuticalcompositions.

In some embodiments, prodrugs include compounds wherein an amino acidresidue, or a polypeptide chain of two or more (e.g., two, three, orfour) amino acid residues is covalently joined through an amide or esterbond to a free amino, hydroxy or carboxylic acid group of compoundsdescribed herein. The amino acid residues include, but are not limitedto, the 20 naturally occurring amino acids and also includes4-hydroxyproline, hydroxylysine, demosine, isodemosine,3-methylhistidine, norvaline, beta-alanine, gamma-aminobutyric acid,cirtulline, homocysteine, homoserine, ornithine and methionine sulfone.In other embodiments, prodrugs include compounds wherein a nucleic acidresidue, or an oligonucleotide of two or more (e.g., two, three or four)nucleic acid residues is covalently joined to a compound describedherein.

Pharmaceutically acceptable prodrugs of the compounds described hereinalso include, but are not limited to, esters, carbonates,thiocarbonates, N-acyl derivatives, N-acyloxyalkyl derivatives,quaternary derivatives of tertiary amines, N-Mannich bases, Schiffbases, amino acid conjugates, phosphate esters, metal salts, andsulfonate esters. In some embodiments, compounds having free amino,amido, hydroxy, or carboxylic groups are converted into prodrugs. Forinstance, free carboxyl groups are derivatized as amides or alkylesters. In certain instances, all of these prodrug moieties incorporategroups including, but not limited to, ether, amine and carboxylic acidfunctionalities.

Hydroxy prodrugs include esters, such as though not limited to,acyloxyalkyl (e.g. acyloxymethyl, acyloxyethyl) esters,alkoxycarbonyloxyalkyl esters, alkyl esters, aryl esters, phosphateesters, sulfonate esters, sulfate esters, and disulfide containingesters; ethers, amides, carbamates, hemi succinates,dimethylaminoacetates and phosphoryloxymethyloxycarbonyls, as outlinedin Advanced Drug Delivery Reviews 1996, 19, 115.

Amine derived prodrugs include, but are not limited to, the followinggroups and combinations of groups:

as well as sulfonamides and phosphonamides.

In certain instances, sites on any aromatic ring portions aresusceptible to various metabolic reactions, therefore incorporation ofappropriate substituents on the aromatic ring structures, reduce,minimize or eliminate this metabolic pathway.

Pharmaceutical Compositions

In certain embodiments, the compound of Formula (I), (II), (III),(IIIa), (IIIb), or (IV) as described herein is administered as a purechemical. In some embodiments, the compound of Formula (I), (II), (III),(IIIa), (IIIb), or (IV) described herein is combined with apharmaceutically suitable or acceptable carrier (also referred to hereinas a pharmaceutically suitable (or acceptable) excipient,physiologically suitable (or acceptable) excipient, or physiologicallysuitable (or acceptable) carrier) selected on the basis of a chosenroute of administration and standard pharmaceutical practice asdescribed, for example, in Remington: The Science and Practice ofPharmacy (Gennaro, 21^(st) Ed. Mack Pub. Co., Easton, Pa. (2005)).

Accordingly, provided herein is a pharmaceutical composition comprisingat least one compound of Formula (I), (II), (III), (IIIa), (IIIb), or(IV) described herein, or a pharmaceutically acceptable salt, solvate,or stereoisomer thereof, together with one or more pharmaceuticallyacceptable carriers. The carrier(s) (or excipient(s)) is acceptable orsuitable if the carrier is compatible with the other ingredients of thecomposition and not deleterious to the recipient (i.e., the subject) ofthe composition.

One embodiment provides a pharmaceutical composition comprising apharmaceutically acceptable excipient and a compound of Formula (I), ora pharmaceutically acceptable salt thereof.

One embodiment provides a pharmaceutical composition comprising apharmaceutically acceptable excipient and a compound of Formula (II), ora pharmaceutically acceptable salt thereof.

One embodiment provides a pharmaceutical composition comprising apharmaceutically acceptable excipient and a compound of Formula (III),or a pharmaceutically acceptable salt thereof.

One embodiment provides a pharmaceutical composition comprising apharmaceutically acceptable excipient and a compound of Formula (IIIa),or a pharmaceutically acceptable salt thereof.

One embodiment provides a pharmaceutical composition comprising apharmaceutically acceptable excipient and a compound of Formula (IIIb),or a pharmaceutically acceptable salt thereof.

One embodiment provides a pharmaceutical composition comprising apharmaceutically acceptable excipient and a compound of Formula (IV), ora pharmaceutically acceptable salt thereof.

Another embodiment provides a pharmaceutical composition consistingessentially of a pharmaceutically acceptable excipient and a compound ofFormula (I), or a pharmaceutically acceptable salt thereof. Anotherembodiment provides a pharmaceutical composition consisting essentiallyof a pharmaceutically acceptable excipient and a compound of Formula(II), or a pharmaceutically acceptable salt thereof. Another embodimentprovides a pharmaceutical composition consisting essentially of apharmaceutically acceptable excipient and a compound of Formula (III),or a pharmaceutically acceptable salt thereof. Another embodimentprovides a pharmaceutical composition consisting essentially of apharmaceutically acceptable excipient and a compound of Formula (IIIa),or a pharmaceutically acceptable salt thereof. Another embodimentprovides a pharmaceutical composition consisting essentially of apharmaceutically acceptable excipient and a compound of Formula (IIIb),or a pharmaceutically acceptable salt thereof. Another embodimentprovides a pharmaceutical composition consisting essentially of apharmaceutically acceptable excipient and a compound of Formula (IV), ora pharmaceutically acceptable salt thereof.

In certain embodiments, the compound of Formula (I), (II), (III),(IIIa), (IIIb), or (IV) as described herein is substantially pure, inthat it contains less than about 5%, or less than about 1%, or less thanabout 0.1%, of other organic small molecules, such as contaminatingintermediates or by-products that are created, for example, in one ormore of the steps of a synthesis method.

These pharmaceutical compositions include those suitable for oral,rectal, topical, buccal, parenteral (e.g., subcutaneous, intramuscular,intradermal, or intravenous), vaginal, ophthalmic, or aerosoladministration.

Exemplary pharmaceutical compositions are used in the form of apharmaceutical preparation, for example, in solid, semisolid, or liquidform, which includes one or more of a disclosed compound, as an activeingredient, in a mixture with an organic or inorganic carrier orexcipient suitable for external, enteral, or parenteral applications. Insome embodiments, the active ingredient is compounded, for example, withthe usual non-toxic, pharmaceutically acceptable carriers for tablets,pellets, capsules, suppositories, solutions, emulsions, suspensions, andany other form suitable for use. The active object compound is includedin the pharmaceutical composition in an amount sufficient to produce thedesired effect upon the process or condition of the disease.

In some embodiments for preparing solid compositions such as tablets,the principal active ingredient is mixed with a pharmaceutical carrier,e.g., conventional tableting ingredients such as corn starch, lactose,sucrose, sorbitol, talc, stearic acid, magnesium stearate, dicalciumphosphate, or gums, and other pharmaceutical diluents, e.g., water, toform a solid preformulation composition containing a homogeneous mixtureof a disclosed compound or a non-toxic pharmaceutically acceptable saltthereof. When referring to these preformulation compositions ashomogeneous, it is meant that the active ingredient is dispersed evenlythroughout the composition so that the composition is readily subdividedinto equally effective unit dosage forms such as tablets, pills, andcapsules.

In solid dosage forms for oral administration (capsules, tablets, pills,dragees, powders, granules, and the like), the subject composition ismixed with one or more pharmaceutically acceptable carriers, such assodium citrate or dicalcium phosphate, and/or any of the following: (1)fillers or extenders, such as starches, cellulose, microcrystallinecellulose, silicified microcrystalline cellulose, lactose, sucrose,glucose, mannitol, and/or silicic acid; (2) binders, such as, forexample, carboxymethylcellulose, hypromellose, alginates, gelatin,polyvinyl pyrrolidone, sucrose, and/or acacia; (3) humectants, such asglycerol; (4) disintegrating agents, such as crospovidone,croscarmellose sodium, sodium starch glycolate, agar-agar, calciumcarbonate, potato or tapioca starch, alginic acid, certain silicates,and sodium carbonate; (5) solution retarding agents, such as paraffin;(6) absorption accelerators, such as quaternary ammonium compounds; (7)wetting agents, such as, for example, docusate sodium, cetyl alcohol,and glycerol monostearate; (8) absorbents, such as kaolin and bentoniteclay; (9) lubricants, such a talc, calcium stearate, magnesium stearate,solid polyethylene glycols, sodium lauryl sulfate, and mixtures thereof;and (10) coloring agents. In the case of capsules, tablets, and pills,in some embodiments, the compositions comprise buffering agents. In someembodiments, solid compositions of a similar type are also employed asfillers in soft and hard-filled gelatin capsules using such excipientsas lactose or milk sugars, as well as high molecular weight polyethyleneglycols and the like.

In some embodiments, a tablet is made by compression or molding,optionally with one or more accessory ingredients. In some embodiments,compressed tablets are prepared using binder (for example, gelatin orhydroxypropylmethyl cellulose), lubricant, inert diluent, preservative,disintegrant (for example, sodium starch glycolate or cross-linkedsodium carboxymethyl cellulose), surface-active or dispersing agent. Insome embodiments, molded tablets are made by molding in a suitablemachine a mixture of the subject composition moistened with an inertliquid diluent. In some embodiments, tablets, and other solid dosageforms, such as dragees, capsules, pills, and granules, are scored orprepared with coatings and shells, such as enteric coatings and othercoatings.

Compositions for inhalation or insufflation include solutions andsuspensions in pharmaceutically acceptable aqueous or organic solvents,or mixtures thereof, and powders. Liquid dosage forms for oraladministration include pharmaceutically acceptable emulsions,microemulsions, solutions, suspensions, syrups, and elixirs. In additionto the subject composition, in some embodiments, the liquid dosage formscontain inert diluents, such as, for example, water or other solvents,solubilizing agents and emulsifiers, such as ethyl alcohol, isopropylalcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzylbenzoate, propylene glycol, 1,3-butylene glycol, oils (in particular,cottonseed, groundnut, corn, germ, olive, castor and sesame oils),glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty acidesters of sorbitan, cyclodextrins, and mixtures thereof.

In some embodiments, suspensions, in addition to the subjectcomposition, contain suspending agents as, for example, ethoxylatedisostearyl alcohols, polyoxyethylene sorbitol and sorbitan esters,microcrystalline cellulose, aluminum metahydroxide, bentonite,agar-agar, tragacanth, and mixtures thereof.

In some embodiments, formulations for rectal or vaginal administrationare presented as a suppository, which are prepared by mixing a subjectcomposition with one or more suitable non-irritating excipients orcarriers comprising, for example, cocoa butter, polyethylene glycol, asuppository wax or a salicylate, and which is solid at room temperature,but liquid at body temperature and, therefore, will melt in the bodycavity and release the active agent.

Dosage forms for transdermal administration of a subject compositioninclude powders, sprays, ointments, pastes, creams, lotions, gels,solutions, patches and inhalants. In some embodiments, the activecomponent is mixed under sterile conditions with a pharmaceuticallyacceptable carrier, and with any preservatives, buffers, or propellantsas required.

In some embodiments, the ointments, pastes, creams and gels contain, inaddition to a subject composition, excipients, such as animal andvegetable fats, oils, waxes, paraffins, starch, tragacanth, cellulosederivatives, polyethylene glycols, silicones, bentonites, silicic acid,talc, and zinc oxide, or mixtures thereof.

In some embodiments, powders and sprays contain, in addition to asubject composition, excipients such as lactose, talc, silicic acid,aluminum hydroxide, calcium silicates and polyamide powder, or mixturesof these substances. In some embodiments, sprays additionally containcustomary propellants, such as chlorofluorohydrocarbons and volatileunsubstituted hydrocarbons, such as butane and propane.

In some embodiments, the compounds described herein are formulated aseye drops for ophthalmic administration.

Compositions and compounds disclosed herein alternatively areadministered by aerosol. This is accomplished by preparing an aqueousaerosol, liposomal preparation or solid particles containing thecompound. In some embodiments, a non-aqueous (e.g., fluorocarbonpropellant) suspension is used. In some embodiments, sonic nebulizersare used because they minimize exposing the agent to shear, whichresults in degradation of the compounds contained in the subjectcompositions. Ordinarily, an aqueous aerosol is made by formulating anaqueous solution or suspension of a subject composition together withconventional pharmaceutically acceptable carriers and stabilizers. Thecarriers and stabilizers vary with the requirements of the particularsubject composition, but typically include non-ionic surfactants(Tweens, Pluronics, or polyethylene glycol), innocuous proteins likeserum albumin, sorbitan esters, oleic acid, lecithin, amino acids suchas glycine, buffers, salts, sugars, or sugar alcohols. Aerosolsgenerally are prepared from isotonic solutions.

Pharmaceutical compositions suitable for parenteral administrationcomprise a subject composition in combination with one or morepharmaceutically-acceptable sterile isotonic aqueous or non-aqueoussolutions, dispersions, suspensions or emulsions, or sterile powderswhich are reconstituted into sterile injectable solutions or dispersionsjust prior to use, which, in some embodiments, contain antioxidants,buffers, bacteriostats, solutes which render the formulation isotonicwith the blood of the intended recipient or suspending or thickeningagents.

Examples of suitable aqueous and non-aqueous carriers which are employedin the pharmaceutical compositions include water, ethanol, polyols (suchas glycerol, propylene glycol, polyethylene glycol, and the like), andsuitable mixtures thereof, vegetable oils such as olive oil, andinjectable organic esters such as ethyl oleate, and cyclodextrins.Proper fluidity is maintained, for example, by the use of coatingmaterials, such as lecithin, by the maintenance of the required particlesize in the case of dispersions, and by the use of surfactants.

Also contemplated are enteral pharmaceutical formulations including adisclosed compound, an enteric material, and a pharmaceuticallyacceptable carrier or excipient thereof. Enteric materials refer topolymers that are substantially insoluble in the acidic environment ofthe stomach, and that are predominantly soluble in intestinal fluids atspecific pHs. The small intestine is the part of the gastrointestinaltract (gut) between the stomach and the large intestine, and includesthe duodenum, jejunum, and ileum. The pH of the duodenum is about 5.5,the pH of the jejunum is about 6.5 and the pH of the distal ileum isabout 7.5. Accordingly, enteric materials are not soluble, for example,until a pH of about 5.0, of about 5.2, of about 5.4, of about 5.6, ofabout 5.8, of about 6.0, of about 6.2, of about 6.4, of about 6.6, ofabout 6.8, of about 7.0, of about 7.2, of about 7.4, of about 7.6, ofabout 7.8, of about 8.0, of about 8.2, of about 8.4, of about 8.6, ofabout 8.8, of about 9.0, of about 9.2, of about 9.4, of about 9.6, ofabout 9.8, or of about 10.0. Exemplary enteric materials includecellulose acetate phthalate (CAP), hydroxypropyl methylcellulosephthalate (HPMCP), polyvinyl acetate phthalate (PVAP), hydroxypropylmethylcellulose acetate succinate (HPMCAS), cellulose acetatetrimellitate, hydroxypropyl methylcellulose succinate, cellulose acetatesuccinate, cellulose acetate hexahydrophthalate, cellulose propionatephthalate, cellulose acetate maleate, cellulose acetate butyrate,cellulose acetate propionate, copolymer of methylmethacrylic acid andmethyl methacrylate, copolymer of methyl acrylate, methylmethacrylateand methacrylic acid, copolymer of methylvinyl ether and maleicanhydride (Gantrez ES series), ethylmethyacrylate-methylmethacrylate-chlorotrimethylammonium ethyl acrylatecopolymer, natural resins such as zein, shellac and copal collophorium,and several commercially available enteric dispersion systems (e.g.,Eudragit L30D55, Eudragit FS30D, Eudragit L100, Eudragit 5100, KollicoatEMM30D, Estacryl 30D, Coateric, and Aquateric). The solubility of eachof the above materials is either known or is readily determinable invitro.

The dose of the composition comprising at least one compound of Formula(I), (II), (III), (IIIa), (IIIb), or (IV) as described herein differs,depending upon the patient's (e.g., human) condition, that is, stage ofthe disease, general health status, age, and other factors.

Pharmaceutical compositions are administered in a manner appropriate tothe disease to be treated (or prevented). An appropriate dose and asuitable duration and frequency of administration will be determined bysuch factors as the condition of the patient, the type and severity ofthe patient's disease, the particular form of the active ingredient, andthe method of administration. In general, an appropriate dose andtreatment regimen provides the composition(s) in an amount sufficient toprovide therapeutic and/or prophylactic benefit (e.g., an improvedclinical outcome, such as more frequent complete or partial remissions,or longer disease-free and/or overall survival, or a lessening ofsymptom severity. Optimal doses are generally determined usingexperimental models and/or clinical trials. In some embodiments, theoptimal dose depends upon the body mass, weight, or blood volume of thepatient.

Oral doses typically range from about 1.0 mg to about 1000 mg, one tofour times, or more, per day.

Methods and Uses

Disclosed herein are in vitro (ex vivo) and in vivo methods ofmodulating the activity of MAGL and/or FAAH. Contemplated methods, forexample, comprise exposing said enzyme to a compound described herein.In some embodiments, the compound utilized by one or more of theforegoing methods is one of the generic, subgeneric, or specificcompounds described herein, such as a compound of Formula (I), (II),(III), (IIIa), (IIIb), or (IV), or a pharmaceutically acceptable salt,solvate, or stereoisomer thereof. The ability of compounds describedherein to modulate or inhibit MAGL and FAAH is evaluated by proceduresknown in the art and/or described herein. Embodiments of the inventionalso relate to a compound of Formula (I), (II), (III), (IIIa), (IIIb),or (IV) described herein and any subgroup thereof, or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, for use in a methodof treating conditions which are characterized by unhealthy or abnormallevels of MAGL and/or FAAH. Conditions “characterized by unhealthy orabnormal levels of MAGL and FAAH” include those like neuropathic pain,anxiety and inflammatory bowel diseases, as well as the proliferationand migration of cancer cells.

In some embodiments is a method of treating pain in a patient in needthereof, comprising administering to the patient a therapeuticallyeffective amount of a compound of Formula (I), (II), (III), (IIIa),(IIIb), or (IV) described herein, or a pharmaceutically acceptable salt,solvate, or stereoisomer thereof. Embodiments of the invention alsorelate to a compound of Formula (I), (II), (III), (IIIa), (IIIb), or(IV) described herein and any subgroup thereof, or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, for use in a methodof treating pain in a patient. In some embodiments is a method oftreating pain in a patient in need thereof, comprising administering tothe patient a therapeutically effective amount of a compound of Formula(I) described herein, or a pharmaceutically acceptable salt, solvate, orstereoisomer thereof. In some embodiments is a method of treating painin a patient in need thereof, comprising administering to the patient atherapeutically effective amount of a compound of Formula (II) describedherein, or a pharmaceutically acceptable salt, solvate, or stereoisomerthereof. In some embodiments is a method of treating pain in a patientin need thereof, comprising administering to the patient atherapeutically effective amount of a compound of Formula (III)described herein, or a pharmaceutically acceptable salt, solvate, orstereoisomer thereof. In some embodiments is a method of treating painin a patient in need thereof, comprising administering to the patient atherapeutically effective amount of a compound of Formula (IIIa)described herein, or a pharmaceutically acceptable salt, solvate, orstereoisomer thereof. In some embodiments is a method of treating painin a patient in need thereof, comprising administering to the patient atherapeutically effective amount of a compound of Formula (IIIb)described herein, or a pharmaceutically acceptable salt, solvate, orstereoisomer thereof. In some embodiments is a method of treating painin a patient in need thereof, comprising administering to the patient atherapeutically effective amount of a compound of Formula (IV) describedherein, or a pharmaceutically acceptable salt, solvate, or stereoisomerthereof.

In some embodiments is a method of treating a neurological disorder in apatient in need thereof, comprising administering to the patient atherapeutically effective amount of a compound of Formula (I), (II),(III), (IIIa), (IIIb), or (IV) described herein, or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof. Embodiments of theinvention also relate to a compound of Formula (I), (II), (III), (IIIa),(IIIb), or (IV) described herein and any subgroup thereof, or apharmaceutically acceptable salt, solvate, or stereoisomer thereof, foruse in a method of treating a neurological disorder in a patient. Insome embodiments is a method of treating a neurological disorder in apatient in need thereof, comprising administering to the patient atherapeutically effective amount of a compound of Formula (I) describedherein, or a pharmaceutically acceptable salt, solvate, or stereoisomerthereof. In some embodiments is a method of treating a neurologicaldisorder in a patient in need thereof, comprising administering to thepatient a therapeutically effective amount of a compound of Formula (II)described herein, or a pharmaceutically acceptable salt, solvate, orstereoisomer thereof. In some embodiments is a method of treating aneurological disorder in a patient in need thereof, comprisingadministering to the patient a therapeutically effective amount of acompound of Formula (III) described herein, or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof. In some embodimentsis a method of treating a neurological disorder in a patient in needthereof, comprising administering to the patient a therapeuticallyeffective amount of a compound of Formula (IIIa) described herein, or apharmaceutically acceptable salt, solvate, or stereoisomer thereof. Insome embodiments is a method of treating a neurological disorder in apatient in need thereof, comprising administering to the patient atherapeutically effective amount of a compound of Formula (IIIb)described herein, or a pharmaceutically acceptable salt, solvate, orstereoisomer thereof. In some embodiments is a method of treating aneurological disorder in a patient in need thereof, comprisingadministering to the patient a therapeutically effective amount of acompound of Formula (IV) described herein, or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof.

In certain embodiments, a disclosed compound utilized by one or more ofthe foregoing methods is one of the generic, subgeneric, or specificcompounds described herein, such as a compound of Formula (I), (II),(III), (IIIa), (IIIb), or (IV). Embodiments of the invention also relateto a compound of Formula (I), (II), (III), (IIIa), (IIIb), or (IV)described herein and any subgroup thereof, or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, for use in one ormore of the foregoing methods of treatment. Embodiments of the inventionalso relate to a compound of Formula (I), (II), (III), (IIIa), (IIIb),or (IV) described herein and any subgroup thereof, or a pharmaceuticallyacceptable salt, solvate, or stereoisomer thereof, for use in a methodof treatment by therapy.

Disclosed compounds are administered to patients (animals and humans) inneed of such treatment in dosages that will provide optimalpharmaceutical efficacy. It will be appreciated that the dose requiredfor use in any particular application will vary from patient to patient,not only with the particular compound or composition selected, but alsowith the route of administration, the nature of the condition beingtreated, the age and condition of the patient, concurrent medication orspecial diets then being followed by the patient, and other factors,with the appropriate dosage ultimately being at the discretion of theattendant physician. For treating clinical conditions and diseases notedabove, a contemplated compound disclosed herein is administered orally,subcutaneously, topically, parenterally, by inhalation spray, orrectally in dosage unit formulations containing conventional non-toxicpharmaceutically acceptable carriers, adjuvants, and vehicles.Parenteral administration include subcutaneous injections, intravenousor intramuscular injections or infusion techniques.

Also contemplated herein are combination therapies, for example,co-administering a disclosed compound and an additional active agent, aspart of a specific treatment regimen intended to provide the beneficialeffect from the co-action of these therapeutic agents. The beneficialeffect of the combination includes, but is not limited to,pharmacokinetic or pharmacodynamic co-action resulting from thecombination of therapeutic agents. Administration of these therapeuticagents in combination typically is carried out over a defined timeperiod (usually weeks, months, or years depending upon the combinationselected). Combination therapy is intended to embrace administration ofmultiple therapeutic agents in a sequential manner, that is, whereineach therapeutic agent is administered at a different time, as well asadministration of these therapeutic agents, or at least two of thetherapeutic agents, in a substantially simultaneous manner.

Substantially simultaneous administration is accomplished, for example,by administering to the subject a single formulation or composition,(e.g., a tablet or capsule having a fixed ratio of each therapeuticagent or in multiple, single formulations (e.g., capsules) for each ofthe therapeutic agents. Sequential or substantially simultaneousadministration of each therapeutic agent is effected by any appropriateroute including, but not limited to, oral routes, intravenous routes,intramuscular routes, and direct absorption through mucous membranetissues. The therapeutic agents are administered by the same route or bydifferent routes. For example, a first therapeutic agent of thecombination selected is administered by intravenous injection while theother therapeutic agents of the combination are administered orally.Alternatively, for example, all therapeutic agents are administeredorally or all therapeutic agents are administered by intravenousinjection.

Combination therapy also embraces the administration of the therapeuticagents as described above in further combination with other biologicallyactive ingredients and non-drug therapies. Where the combination therapyfurther comprises a non-drug treatment, the non-drug treatment isconducted at any suitable time so long as a beneficial effect from theco-action of the combination of the therapeutic agents and non-drugtreatment is achieved. For example, in appropriate cases, the beneficialeffect is still achieved when the non-drug treatment is temporallyremoved from the administration of the therapeutic agents, perhaps bydays or even weeks.

The components of the combination are administered to a patientsimultaneously or sequentially. It will be appreciated that thecomponents are present in the same pharmaceutically acceptable carrierand, therefore, are administered simultaneously. Alternatively, theactive ingredients are present in separate pharmaceutical carriers, suchas conventional oral dosage forms, that are administered eithersimultaneously or sequentially.

For example, e.g., for contemplated treatment of pain, a disclosedcompound is co-administered with another therapeutic for pain such as anopioid, a cannabinoid receptor (CB-1 or CB-2) modulator, a COX-2inhibitor, acetaminophen, and/or a non-steroidal anti-inflammatoryagent. Additional therapeutics e.g., for the treatment of pain that areco-administered, include morphine, codeine, hydromorphone, hydrocodone,oxymorphone, fentanyl, tramadol, and levorphanol.

Other contemplated therapeutics for co-administration include aspirin,naproxen, ibuprofen, salsalate, diflunisal, dexibuprofen, fenoprofen,ketoprofen, oxaprozin, loxoprofen, indomethacin, tolmetin, sulindac,etodolac, ketorolac, piroxicam, meloxicam, tenoxicam, droxicam,lornoxicam, celecoxib, parecoxib, rimonabant, and/or etoricoxib.

The following examples are provided merely as illustrative of variousembodiments and shall not be construed to limit the invention in anyway.

EXAMPLES List of Abbreviations

As used above, and throughout the description of the invention, thefollowing abbreviations, unless otherwise indicated, shall be understoodto have the following meanings:

-   -   ACN or MeCN acetonitrile    -   Bn benzyl    -   BOC or Boc tert-butyl carbamate    -   CDI 1,1′-carbonyldiimidazole    -   Cy cyclohexyl    -   DCE dichloroethane (ClCH₂CH₂Cl)    -   DCM dichloromethane (CH₂Cl₂)    -   DIPEA or DIEA diisopropylethylamine    -   DMAP 4-(N,N-dimethylamino)pyridine    -   DMF dimethylformamide    -   DMA N,N-dimethylacetamide    -   DMSO dimethylsulfoxide    -   equiv equivalent(s)    -   Et ethyl    -   EtOH ethanol    -   EtOAc ethyl acetate    -   HATU        1-[bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b]pyridinium        3-oxid hexafluorophosphate    -   HPLC high performance liquid chromatography    -   LAH lithium aluminum hydride    -   Me methyl    -   MeOH methanol    -   MS mass spectroscopy    -   NMM N-methylmorpholine    -   NMR nuclear magnetic resonance    -   PMB para-methoxybenzyl    -   TEA triethylamine    -   TFA trifluoroacetic acid    -   THF tetrahydrofuran    -   TLC thin layer chromatography

I. Chemical Synthesis

Unless otherwise noted, reagents and solvents were used as received fromcommercial suppliers. Anhydrous solvents and oven-dried glassware wereused for synthetic transformations sensitive to moisture and/or oxygen.Yields were not optimized. Reaction times are approximate and were notoptimized. Column chromatography and thin layer chromatography (TLC)were performed on silica gel unless otherwise noted. Spectra are givenin ppm (δ) and coupling constants (J) are reported in Hertz. For protonspectra the solvent peak was used as the reference peak.

Example 1: 5-(Trifluoromethyl)pyridin-3-yl2-(3-(trifluoromethyl)phenoxy)-7-azaspiro[3.5]nonane-7-carboxylate

Step 1: Preparation of tert-butyl2-((methylsulfonyl)oxy)-7-azaspiro[3.5]nonane-7-carboxylate

A 250-mL round-bottom flask was charged with tert-butyl2-hydroxy-7-azaspiro[3.5]nonane-7-carboxylate (3.00 g, 12.4 mmol, 1.00equiv), triethylamine (3.77 g, 37.3 mmol, 3.00 equiv), anddichloromethane (50 mL). Methanesulfonyl chloride (2.13 g, 18.7 mmol,1.50 equiv) was added at 0° C. The reaction was stirred overnight atroom temperature and quenched with water (100 mL). The resultingsolution was extracted with dichloromethane (3×100 mL) and the organiclayers were combined, washed with brine (3×100 mL), dried over anhydroussodium sulfate, filtered, and concentrated under reduced pressure toprovide 4.55 g of tert-butyl2-((methylsulfonyl)oxy)-7-azaspiro[3.5]nonane-7-carboxylate as a brownoil. LCMS (ESI, m/z): 320 [M+H]⁺.

Step 2: Preparation of tert-butyl2-(3-(trifluoromethyl)phenoxy)-7-azaspiro[3.5]nonane-7-carboxylate

A 50-mL round-bottom flask was charged with tert-butyl2-((methylsulfonyl)oxy)-7-azaspiro[3.5]nonane-7-carboxylate (0.909 g,2.85 mmol, 1.00 equiv), 3-(trifluoromethyl)phenol (0.554 g, 3.42 mmol,1.20 equiv), cesium carbonate (2.79 g, 8.55 mmol, 3.00 equiv), and DMF(20 mL). The reaction was stirred overnight at 80° C. and quenched withwater (20 mL). The resulting solution was extracted with ethyl acetate(3×20 mL) and the organic layers were combined, washed with brine (1×100mL), dried over anhydrous sodium sulfate, filtered, and concentratedunder reduced pressure. The residue was chromatographed on a silica gelcolumn to provide 0.880 g (80% yield) of tert-butyl2-(3-(trifluoromethyl)phenoxy)-7-azaspiro[3.5]nonane-7-carboxylate as alight yellow oil. LCMS (ESI, m/z): 386 [M+H]⁺.

Step 3: Preparation of2-(3-(trifluoromethyl)phenoxy)-7-azaspiro[3.5]nonane

A 50-mL round-bottom flask was charged with tert-butyl2-(3-(trifluoromethyl)phenoxy)-7-azaspiro[3.5]nonane-7-carboxylate (880mg, 2.28 mmol, 1.00 equiv), dichloromethane (20 mL), and trifluoroaceticacid (12 mL). The resulting solution was stirred for 2 hours at roomtemperature and concentrated under reduced pressure. The crude productwas dissolved in 1M sodium hydroxide solution (10 mL) and extracted withdichloromethane (3×20 mL). The organic layers were combined, washed withbrine (10 mL), dried over anhydrous sodium sulfate, filtered, andconcentrated under reduced pressure to provide 638 mg (98% yield) of2-(3-(trifluoromethyl)phenoxy)-7-azaspiro[3.5]nonane as a yellow oil.LCMS (ESI, m/z): 286 [M+H]⁺.

Step 4: Preparation of 5-(trifluoromethyl)pyridin-3-yl2-(3-(trifluoromethyl)phenoxy)-7-azaspiro[3.5]nonane-7-carboxylate

A 50-mL round-bottom flask was charged with triphosgene (158 mg, 0.530mmol, 0.70 equiv) and dichloromethane (20 mL).5-(Trifluoromethyl)pyridin-3-ol (248 mg, 1.52 mmol, 2.00 equiv) andpyridine were added in sequence at 0° C., and the mixture continued tostir for 2 hours at 0° C. before the addition of2-(3-(trifluoromethyl)phenoxy)-7-azaspiro[3.5]nonane (217 mg, 0.760mmol, 1.00 equiv). The resulting solution was stirred overnight at roomtemperature and quenched with water (20 mL). The mixture was extractedwith dichloromethane (3×20 mL) and the organic layers were combined,washed with brine (1×100 mL), dried over anhydrous sodium sulfate,filtered, and concentrated under reduced pressure. The crude product(900 mg) was purified by preparative HPLC to afford 206.5 mg (57% yield)of 5-(trifluoromethyl)pyridin-3-yl2-(3-(trifluoromethyl)phenoxy)-7-azaspiro[3.5]nonane-7-carboxylate as abrown oil. ¹H NMR (300 MHz, Chloroform-d) δ 8.75 (s, 1H), 8.66 (s, 1H),7.81 (s, 1H), 7.38-7.43 (m, 1H), 7.22-7.25 (m, 1H), 6.99-7.04 (m, 2H),4.74-4.82 (m, 1H), 3.51-3.68 (m, 4H), 2.49-2.56 (m, 2H), 2.03-2.10 (m,2H), 1.78 (s, 4H). LCMS (ESI, m/z): 516 [M+H+MeCN]⁺.

Example 2: 5-(Trifluoromethyl)pyridin-3-yl2-(4-(3-chlorophenoxy)benzyl)-2,7-diazaspiro[3.5]nonane-7-carboxylate

Step 1: Preparation of 3-(benzyloxy)-5-(trifluoromethyl)pyridine

A 250-mL 3-necked round-bottom flask was charged with3-chloro-5-(trifluoromethyl)pyridine (5.04 g, 27.5 mmol, 1.00 equiv),phenylmethanol (2.98 g, 27.6 mmol, 1.00 equiv), and DMF (30 mL) undernitrogen. Sodium hydride (60% dispersion in mineral oil, 2.32 g, 55.8mmol, 2.00 equiv) was added portion-wise at 0° C. The resulting solutionwas stirred for 2 hours at 40° C. and quenched with water (20 mL). Themixture was extracted with dichloromethane (3×30 mL) and the organiclayers were combined, washed with water (3×30 mL), dried over anhydroussodium sulfate, filtered, and concentrated under reduced pressure toprovide 3.00 g (43% yield) of 3-(benzyloxy)-5-(trifluoromethyl)pyridineas a yellow oil. LCMS (ESI, m/z): 254 [M+H]⁺.

Step 2: Preparation of 5-(trifluoromethyl)pyridin-3-ol

A 250-mL 3-necked round-bottom flask was charged with3-(benzyloxy)-5-(trifluoromethyl)pyridine (3.00 g, 11.9 mmol, 1.00equiv), methanol (30 mL) and 10% palladium carbon (150 mg). Theresulting solution was stirred for 4 hours at 50° C. under hydrogen.Solids were filtered and washed with methanol (3×30 mL). The filtratewas concentrated under reduced pressure to provide 1.60 g (83% yield) of5-(trifluoromethyl)pyridin-3-ol as a white solid. LCMS (ESI, m/z): 164[M+H]⁺.

Step 3: Preparation of 2-(tert-butyl)7-(5-(trifluoromethyl)pyridin-3-yl)2,7-diazaspiro[3.5]nonane-2,7-dicarboxylate

A 100-mL round-bottom flask was charged with triphosgene (0.971 mg, 3.27mmol, 0.37 equiv), 5-(trifluoromethyl)pyridin-3-yl chloroformate (2.08g, 8.87 mmol, 1.10 equiv) and dichloromethane (30 mL). Pyridine (1.94 g,24.5 mmol, 3.00 equiv) was added dropwise at 0° C. The resultingsolution was stirred for 2 hours at 0° C. prior to addition oftert-butyl 2,7-diazaspiro[3.5]nonane-2-carboxylate (1.85 g, 8.17 mmol,1.00 equiv). The reaction was stirred overnight at room temperature andquenched with water (10 mL). The mixture was extracted withdichloromethane (3×20 mL) and the organic layers were combined, washedwith water (3×20 mL), dried over anhydrous sodium sulfate, filtered, andconcentrated under reduced pressure. The residue was chromatographed ona silica gel column to provide 1.40 g (41% yield) of 2-(tert-butyl)7-(5-(trifluoromethyl)pyridin-3-yl)2,7-diazaspiro[3.5]nonane-2,7-dicarboxylate as a yellow oil. LCMS (ESI,m/z): 416 [M+H]⁺.

Step 4: Preparation of 5-(trifluoromethyl)pyridin-3-yl2,7-diazaspiro[3.5]nonane-7-carboxylate

A 100-mL round-bottom flask was charged with 2-(tert-butyl)7-(5-(trifluoromethyl)pyridin-3-yl)2,7-diazaspiro[3.5]nonane-2,7-dicarboxylate (1.40 g, 3.37 mmol, 1.00equiv), dichloromethane (20 mL) and trifluoroacetic acid (10 mL). Theresulting solution was stirred for 2 hours at room temperature andconcentrated under reduced pressure to provide 1.02 g of5-(trifluoromethyl)pyridin-3-yl 2,7-diazaspiro[3.5]nonane-7-carboxylateas a yellow oil. LCMS (ESI, m/z): 316 [M+H]⁺.

Step 5: Preparation of 5-(trifluoromethyl)pyridin-3-yl2-(4-(3-chlorophenoxy)benzyl)-2,7-diazaspiro[3.5]nonane-7-carboxylate

A 40-mL round-bottom flask was charged with4-(3-chlorophenoxy)benzaldehyde (100 mg, 0.431 mmol, 1.00 equiv),5-(trifluoromethyl)pyridin-3-yl 2,7-diazaspiro[3.5]nonane-7-carboxylate(164 mg, 0.522 mmol, 1.20 equiv), triethylamine (130 mg, 1.28 mmol, 3.0equiv), and 1,2-dichloroethane (10 mL). The resulting solution wasstirred for 2 hours at room temperature prior to addition of sodiumtriacetoxyborohydride (228 mg, 1.08 mmol, 2.50 equiv). The reaction wasstirred overnight at room temperature and quenched with water (10 mL).The mixture was extracted with dichloromethane (3×10 mL) and the organiclayers were combined, washed with water (3×10 mL), dried over anhydroussodium sulfate, filtered, and concentrated under reduced pressure. Thecrude product was purified by preparative HPLC to afford 36.4 mg (16%yield) of 5-(trifluoromethyl)pyridin-3-yl2-(4-(3-chlorophenoxy)benzyl)-2,7-diazaspiro[3.5]nonane-7-carboxylate asa colorless oil. ¹H NMR (300 MHz, Chloroform-d) δ 8.72 (s, 1H), 8.62 (s,1H), 7.77 (s, 1H), 7.28-7.31 (m, 2H), 7.22-7.27 (m, 1H), 7.05-7.12 (m,1H), 6.90-7.00 (m, 3H), 6.88-6.90 (m, 1H), 3.68 (s, 2H), 3.61 (br, 2H),3.50 (br, 2H), 3.04-3.15 (m, 4H), 1.87 (br, 4H). LCMS (ESI, m/z): 532[M+H]⁺.

Example 3: 5-Carbamoylpyridin-3-yl2-(3-chloro-5-(trifluoromethyl)benzyl)-2,8-diazaspiro[4.5]decane-8-carboxylate

Step 1: Preparation of tert-butyl2-(3-chloro-5-(trifluoromethyl)benzyl)-2,8-diazaspiro[4.5]decane-8-carboxylate

A 250-mL round-bottom flask was charged with3-chloro-5-(trifluoromethyl)benzaldehyde (2.08 g, 10.0 mmol, 1.00equiv), tert-butyl 2,8-diazaspiro[4.5]decane-8-carboxylate (2.40 g, 10.0mmol, 1.00 equiv), and 1,2-dichloroethane (50 mL). The resultingsolution was stirred for 2 hours at room temperature prior to additionof sodium triacetoxyborohydride (4.24 g, 20.0 mmol, 2.00 equiv). Thereaction was stirred overnight at room temperature and quenched withwater (150 mL). The mixture was extracted with dichloromethane (3×100mL) and the organic layers were combined, washed with brine (3×100 mL),dried over anhydrous sodium sulfate, filtered, and concentrated underreduced pressure. The residue was chromatographed on a silica gel toprovide 3.67 g (90% yield) of tert-butyl2-(3-chloro-5-(trifluoromethyl)benzyl)-2,8-diazaspiro[4.5]decane-8-carboxylateas a white solid. LCMS (ESI, m/z): 433 [M+H]⁺.

Step 2: Preparation of2-(3-chloro-5-(trifluoromethyl)benzyl)-2,8-diazaspiro[4.5]decane

A 100-mL round-bottom flask was charged with tert-butyl2-(3-chloro-5-(trifluoromethyl)benzyl)-2,8-diazaspiro[4.5]decane-8-carboxylate(3.67 g, 9.20 mmol, 1.00 equiv), concentrated hydrochloric acid (10 mL)and 1,4-dioxane (20 mL). The resulting solution was stirred for 3 hoursat room temperature and concentrated under reduced pressure to provide2.82 g of2-(3-chloro-5-(trifluoromethyl)benzyl)-2,8-diazaspiro[4.5]decane as awhite solid. LCMS (ESI, m/z): 333 [M+H]⁺.

Step 3: Preparation of 5-carbamoylpyridin-3-yl2-(3-chloro-5-(trifluoromethyl)benzyl)-2,8-diazaspiro[4.5]decane-8-carboxylate

A 40-mL vial was charged with 5-hydroxypyridine-3-carboxamide (207 mg,1.50 mmol, 1.50 equiv), triphosgene (93.0 mg, 0.330 mmol, 0.33 equiv)and tetrahydrofuran (5 mL). Pyridine (395 mg, 4.99 mmol, 5.00 equiv) wasadded dropwise at 0° C. and the resulting solution was stirred for 3hours at 0° C.2-(3-chloro-5-(trifluoromethyl)benzyl)-2,8-diazaspiro[4.5]decane (333mg, 1.00 mmol, 1.00 equiv) was combined with sodium hydride (60%dispersion in mineral oil, 48.0 mg, 1.20 mol, 1.20 equiv) intetrahydrofuran (5 mL) and this solution was added to the reaction. Thereaction was stirred overnight at room temperature and quenched withwater (20 mL). The mixture was extracted with ethyl acetate (3×10 mL)and the organic layers were combined, washed with brine (3×10 mL), driedover anhydrous sodium sulfate, filtered, and concentrated under reducedpressure. The crude product was purified by preparative HPLC to provide50.1 mg (10% yield) of 5-carbamoylpyridin-3-yl2-(3-chloro-5-(trifluoromethyl)benzyl)-2,8-diazaspiro[4.5]decane-8-carboxylateas a white solid. ¹H NMR (300 MHz, Chloroform-d) δ 8.83 (s, 1H), 8.57(d, J=2.3 Hz, 1H), 7.96 (t, J=2.2 Hz, 1H), 7.50-7.61 (m, 3H), 6.29 (br,1H), 5.91 (br, 1H), 3.45-3.70 (m, 6H), 2.64 (br, 2H), 2.44 (br, 2H),1.67-1.76 (m, 6H). LCMS (ESI, m/z): 497 [M+H]⁺.

Example 4: 5-Carbamoylpyridin-3-yl2-(5-chloro-2-(trifluoromethyl)benzyl)-2,8-diazaspiro[4.5]decane-8-carboxylate

Step 1: Preparation of tert-butyl2-(5-chloro-2-(trifluoromethyl)benzyl)-2,8-diazaspiro[4.5]decane-8-carboxylate

A 250-mL round-bottom flask was charged with5-chloro-2-(trifluoromethyl)benzaldehyde (0.860 g, 4.12 mmol, 1.00equiv), tert-butyl 2,8-diazaspiro[4.5]decane-8-carboxylate (1.00 g, 4.16mmol, 1.00 equiv), and 1,2-dichloroethane (50 mL). The mixture wasstirred for 2 hours at room temperature prior to addition of sodiumtriacetoxyborohydride (3.90 g, 18.4 mmol, 2.00 equiv). The resultingsolution was stirred overnight at room temperature and quenched withwater (50 mL). The mixture was extracted with dichloromethane (3×50 mL)and the organic layers were combined, washed with water (3×50 mL), driedover anhydrous sodium sulfate, filtered, and concentrated under reducedpressure. The residue was chromatographed on a silica gel column toprovide 1.50 g (84% yield) of tert-butyl2-(5-chloro-2-(trifluoromethyl)benzyl)-2,8-diazaspiro[4.5]decane-8-carboxylateas a white oil. LCMS (ESI, m/z): 433 [M+H]⁺.

Step 2: Preparation of2-(5-chloro-2-(trifluoromethyl)benzyl)-2,8-diazaspiro[4.5]decane

A 250-mL round-bottom flask was charged with tert-butyl2-(5-chloro-2-(trifluoromethyl)benzyl)-2,8-diazaspiro[4.5]decane-8-carboxylate(1.50 g, 3.46 mmol, 1.00 equiv), 1,4-dioxane (50 mL) and concentratedhydrogen chloride (20 mL). The resulting solution was stirred for 2hours at room temperature and concentrated under reduced pressure toprovide 1.20 g of2-(5-chloro-2-(trifluoromethyl)benzyl)-2,8-diazaspiro[4.5]decane as awhite solid. LCMS (ESI, m/z): 333 [M+H]⁺.

Step 3: Preparation of2-(5-chloro-2-(trifluoromethyl)benzyl)-2,8-diazaspiro[4.5]decane-8-carbonylchloride

A 40-mL round-bottom flask was charged with2-(5-chloro-2-(trifluoromethyl)benzyl)-2,8-diazaspiro[4.5]decane (1.00g, 3.00 mmol, 1.00 equiv), triphosgene (0.358 g, 1.21 mmol, 0.40 equiv)and dichloromethane (10 mL). DIPEA (0.777 g, 6.01 mmol, 2.00 equiv) wasadded dropwise at 0° C., and the resulting solution was stirred for 2hours at 0° C. before quenching with water (5 mL). The mixture wasextracted with dichloromethane (3×10 mL) and the organic layers werecombined, washed with water (3×10 mL), dried over anhydrous sodiumsulfate, filtered, and concentrated under reduced pressure to provide1.18 g of2-(5-chloro-2-(trifluoromethyl)benzyl)-2,8-diazaspiro[4.5]decane-8-carbonylchloride as a yellow oil.

Step 4: Preparation of 5-carbamoylpyridin-3-yl2-(5-chloro-2-(trifluoromethyl)benzyl)-2,8-diazaspiro[4.5]decane-8-carboxylate

A 40-mL vial was charged with 5-hydroxypyridine-3-carboxamide (83.0 mg,0.600 mmol, 1.00 equiv), sodium hydride (60% dispersion in mineral oil,120 mg, 3.00 mmol, 3.00 equiv), and tetrahydrofuran (10 mL) undernitrogen. The mixture was stirred for 2 hours at room temperature priorto addition of2-(5-chloro-2-(trifluoromethyl)benzyl)-2,8-diazaspiro[4.5]decane-8-carbonylchloride (237 mg, 0.600 mmol, 1.00 equiv). The resulting solution wasstirred overnight at 60° C. and quenched with water (30 mL). The mixturewas extracted with dichloromethane (3×20 mL), and the organic layerswere combined, washed with water (3×20 mL), dried over anhydrous sodiumsulfate, filtered, and concentrated under reduced pressure. The crudeproduct was purified by preparative HPLC to provide 42.6 mg (14% yield)of 5-carbamoylpyridin-3-yl2-(5-chloro-2-(trifluoromethyl)benzyl)-2,8-diazaspiro[4.5]decane-8-carboxylateas a white solid. ¹H NMR (300 MHz, Chloroform-d) δ 8.84 (d, J=1.8 Hz,1H), 8.60 (d, J=2.4 Hz, 1H), 7.98-8.00 (m, 1H), 7.84-7.86 (m, 1H), 7.60(d, J=8.4 Hz, 1H), 7.28-7.36 (m, 1H), 5.70-6.40 (m, 2H), 3.50-3.80 (m,6H), 2.50-2.72 (m, 4H), 1.66-1.74 (m, 6H). LCMS (ESI, m/z): 497 [M+H]⁺.

Example 5: 5-Carbamoylpyridin-3-yl2-(3-(4-chlorophenoxy)benzyl)-2,7-diazaspiro[3.5]nonane-7-carboxylate

Step 1: Preparation of 5-carbamoylpyridin-3-yl (4-nitrophenyl) carbonate

A 40-mL vial was charged with 5-hydroxypyridine-3-carboxamide (138 mg,1.00 mmol, 1.00 equiv), pyridine (158 mg, 2.00 mmol, 2.00 equiv) andacetonitrile (5 mL). 4-Nitrophenyl chloroformate (222 mg, 1.10 mmol,1.10 equiv) was added at 0° C. The resulting solution was stirred for 2hours at 0° C. and concentrated under reduced pressure to provide 303 mgof 5-carbamoylpyridin-3-yl (4-nitrophenyl) carbonate as a yellow solid.

Step 2: Preparation of tert-butyl2-(3-(4-chlorophenoxy)benzyl)-2,7-diazaspiro[3.5]nonane-7-carboxylate

A 100-mL round-bottom flask was charged with tert-butyl2,7-diazaspiro[3.5]nonane-7-carboxylate (452 mg, 2.00 mmol, 1.00 equiv),3-(4-chlorophenoxy)benzaldehyde (466 mg, 2.00 mmol, 1.00 equiv) and1,2-dichloroethane (10 mL). The mixture was stirred for 2 h at roomtemperature prior to addition of sodium triacetoxyborohydride (848 mg,4.00 mmol, 2.00 equiv). The resulting solution was stirred overnight atroom temperature and quenched with water (50 mL). The mixture wasextracted with dichloromethane (3×50 mL) and the organic layers werecombined, washed with brine (3×50 mL), dried over anhydrous sodiumsulfate, filtered, and concentrated under reduced pressure. The residuewas chromatographed on a silica gel column to provide 700 mg (79% yield)of tert-butyl2-(3-(4-chlorophenoxy)benzyl)-2,7-diazaspiro[3.5]nonane-7-carboxylate asa white semi-solid. LCMS (ESI, m/z): 443 [M+H]⁺.

Step 3: Preparation of2-(3-(4-chlorophenoxy)benzyl)-2,7-diazaspiro[3.5]nonane

A 100-mL round-bottom flask was charged with tert-butyl2-(3-(4-chlorophenoxy)benzyl)-2,7-diazaspiro[3.5]nonane (443 mg, 1.00mmol, 1.00 equiv), 1,4-dioxane (20 mL) and concentrated hydrogenchloride (5 mL). The resulting solution was stirred for 4 hours at roomtemperature and concentrated under reduced pressure to provide 343 mg of2-(3-(4-chlorophenoxy)benzyl)-2,7-diazaspiro[3.5]nonane as a whitesolid. LCMS (ESI, m/z): 343 [M+H]⁺.

Step 4: Preparation of 5-carbamoylpyridin-3-yl2-(3-(4-chlorophenoxy)benzyl)-2,7-diazaspiro[3.5]nonane-7-carboxylate

A 40-mL vial was charged with2-(3-(4-chlorophenoxy)benzyl)-2,7-diazaspiro[3.5]nonane (343 mg, 1.00mmol, 1.00 equiv), tetrahydrofuran (5 mL) and sodium hydride (60%dispersion in mineral oi, 100 mg, 2.50 mmol, 2.50 equiv) under nitrogen.The resulting solution was stirred for 30 minutes at room temperatureprior to addition of 5-carbamoylpyridin-3-yl 4-nitrophenyl carbonate(303 mg, 1.00 mmol, 1.00 equiv). The reaction was stirred overnight at60° C. and quenched with water (10 mL). The mixture was extracted withethyl acetate (3×10 mL) and the organic layers were combined, washedwith brine (3×10 mL), dried over anhydrous sodium sulfate, filtered, andconcentrated under reduced pressure. The crude product was purified bypreparative HPLC to provide 21.2 mg (4% yield) of5-carbamoylpyridin-3-yl2-(3-(4-chlorophenoxy)benzyl)-2,7-diazaspiro[3.5]nonane-7-carboxylate asa white solid. ¹H NMR (300 MHz, Chloroform-d) δ 8.83 (d, J=1.8 Hz, 1H),8.57 (d, J=2.5 Hz, 1H), 7.94 (t, J=2.2 Hz, 1H), 7.26-7.32 (m, 3H),7.05-7.08 (m, 1H), 6.86-6.96 (m, 4H), 6.23 (br, 1H), 5.78 (br, 1H),3.39-3.74 (m, 6H), 3.27 (br, 4H), 1.87 (br, 4H). LCMS (ESI, m/z): 507[M+H]⁺.

Example 6: 5-Aminopyridin-3-yl4-(4-chloro-3-isopropoxybenzyl)piperazine-1-carboxylate

Step 1: Preparation of 4-chloro-3-isopropoxybenzaldehyde

A 250-mL round-bottom flask was charged with4-chloro-3-hydroxybenzaldehyde (2.00 g, 12.8 mmol, 1.00 equiv),2-iodopropane (4.30 g, 25.3 mmol, 2.00 equiv), cesium carbonate (12.4 g,38.1 mmol, 3.00 equiv) and DMF (80 mL). The resulting solution wasstirred overnight at 80° C. and quenched with water (50 mL). The mixturewas extracted with ethyl acetate (3×100 mL) and the organic layers werecombined, washed with water (3×30 mL), dried over anhydrous sodiumsulfate, filtered, and concentrated under reduced pressure. The residuewas chromatographed on a silica gel column to provide 2.37 g (93% yield)of 4-chloro-3-isopropoxybenzaldehyde as a yellow oil. LCMS (ESI, m/z):199 [M+H]⁺.

Step 2: Preparation of tert-butyl4-(4-chloro-3-isopropoxybenzyl)piperazine-1-carboxylate

A 100-mL round-bottom flask was charged with4-chloro-3-isopropoxybenzaldehyde (1.00 g, 5.03 mmol, 1.00 equiv),tert-butyl piperazine-1-carboxylate (1.40 g, 7.52 mmol, 1.50 equiv) and1,2-dichloroethane (30 mL). The resulting solution was stirred for 1hour at room temperature prior to addition of sodiumtriacetoxyborohydride (2.20 g, 10.4 mmol, 2.00 equiv). The reaction wasstirred overnight at room temperature and quenched with water (30 mL).The mixture was extracted with dichloromethane (3×50 mL), and theorganic layers were combined, washed with water (3×30 mL), dried overanhydrous sodium sulfate, filtered, and concentrated under reducedpressure. The residue was chromatographed on a silica gel column toprovide 1.49 g (80% yield) of tert-butyl4-(4-chloro-3-isopropoxybenzyl)piperazine-1-carboxylate as a yellow oil.LCMS (ESI, m/z): 369 [M+H]⁺.

Step 3: Preparation of 1-(4-chloro-3-isopropoxybenzyl)piperazine

A 50-mL round-bottom flask was charged with tert-butyl4-(4-chloro-3-isopropoxybenzyl)piperazine-1-carboxylate (1.11 g, 3.00mmol, 1.00 equiv), trifluoroacetic acid (1 mL) and dichloromethane (10mL). The resulting solution was stirred for 3 hours at room temperatureand concentrated under reduced pressure to provide 0.807 g of1-(4-chloro-3-isopropoxybenzyl)piperazine as a yellow oil. LCMS (ESI,m/z): 269 [M+H]⁺.

Step 4: Preparation of4-(4-chloro-3-isopropoxybenzyl)piperazine-1-carbonyl chloride

A 50-mL round-bottom flask was charged with1-(4-chloro-3-isopropoxybenzyl)piperazine (538 mg, 2.00 mmol, 1.00equiv), triphosgene (298 mg, 1.00 mmol, 0.50 equiv), and dichloromethane(10 mL). DIPEA (516 mg, 4.00 mmol, 2.00 equiv) was added dropwise at 0°C. The resulting solution was stirred for 3 hours at room temperatureand quenched with water (10 mL). The mixture was extracted withdichloromethane (3×30 mL) and the organic layers were combined, washedwith water (3×10 mL), dried over anhydrous sodium sulfate, filtered, andconcentrated under reduced pressure to provide 662 mg of4-(4-chloro-3-isopropoxybenzyl)piperazine-1-carbonyl chloride as ayellow solid.

Step 5: Preparation of 5-aminopyridin-3-yl4-(4-chloro-3-isopropoxybenzyl)piperazine-1-carboxylate

A 50-mL round-bottom flask was charged with4-(4-chloro-3-isopropoxybenzyl)piperazine-1-carbonyl chloride (390 mg,1.18 mmol, 1.20 equiv), 5-aminopyridin-3-ol (108 mg, 0.980 mmol, 1.00equiv), 4-dimethylaminopyridine (23.9 mg, 0.200 mmol, 0.20 equiv), DIPEA(457 mg, 3.54 mmol, 3.00 equiv) and tetrahydrofuran (10 mL). Theresulting solution was stirred overnight at 60° C. and quenched withwater (10 mL). The mixture was extracted with ethyl acetate (3×30 mL)and the organic layers were combined, washed with water (3×10 mL), driedover anhydrous sodium sulfate, filtered, and concentrated under reducedpressure. The crude product was purified by preparative HPLC to afford249.0 mg (63% yield) of 5-aminopyridin-3-yl4-(4-chloro-3-isopropoxybenzyl)piperazine-1-carboxylate as a yellowsolid. ¹H NMR: (300 MHz, Chloroform-d) δ 7.71-7.93 (m, 2H), 7.34-7.38(m, 1H), 6.89-7.01 (s, 1H), 6.74-6.89 (m, 2H), 4.42-4.71 (m, 1H),3.34-3.90 (m, 8H), 2.30-2.61 (m, 4H), 1.24-1.40 (m, 6H). LCMS (ESI,m/z): 405 [M+H]⁺.

Example 7: 5-(Trifluoromethyl)pyridin-3-yl2-(3-(benzo[d]thiazol-2-yloxy)benzyl)-2,7-diazaspiro[3.5]nonane-7-carboxylate

Step 1: Preparation of 3-(benzo[d]thiazol-2-yloxy)benzaldehyde

A 100-mL round-bottom flask was charged with 3-hydroxybenzaldehyde (1.00g, 8.20 mmol, 1.00 equiv), 2-chlorobenzo[d]thiazole (2.08 g, 12.3 mmol,1.50 equiv), DMF (25 mL), and potassium carbonate (3.40 g, 24.6 mmol,3.00 equiv) under nitrogen. The reaction was stirred overnight at 80° C.and quenched with water (25 mL). The resulting solution was extractedwith ethyl acetate (3×25 mL) and the organic layers were combined,washed with brine (2×50 mL), dried over anhydrous sodium sulfate,filtered, and concentrated under reduced pressure. The residue waschromatographed on a silica gel column to provide 0.800 g (38% yield) of3-(benzo[d]thiazol-2-yloxy)benzaldehyde as a yellow oil. LCMS (ESI,m/z): 256 [M+H]⁺.

Step 2: Preparation of 2-(tert-butyl)7-(5-(trifluoromethyl)pyridin-3-yl)2,7-diazaspiro[3.5]nonane-2,7-dicarboxylate

A 100-mL round-bottom flask was charged with triphosgene (0.986 g, 3.32mmol, 0.50 equiv), and tetrahydrofuran (15 mL). tert-Butyl2,7-diazaspiro[3.5]nonane-2-carboxylate (1.50 g, 6.64 mmol, 1.00 equiv)was added at 0° C. followed by DIPEA (3.43 g, 26.6 mmol, 4.00 equiv).The reaction was stirred for 2 hours at room temperature and quenchedwith water (15 mL). The resulting solution was extracted withdichloromethane (3×15 mL) and the organic layers were combined, washedwith brine (2×50 mL), dried over anhydrous sodium sulfate, filtered, andconcentrated under reduced pressure. The crude product was dissolved intetrahydrofuran (15 mL) and 5-(trifluoromethyl)pyridin-3-ol (1.30 g,7.97 mmol, 1.20 equiv) and potassium tert-butoxide (1.12 g, 9.96 mmol,1.50 equiv) were added. The resulting solution was stirred overnight atroom temperature and quenched with water (15 mL). The mixture wasextracted with dichloromethane (3×100 mL) and the organic layers werecombined, washed with brine (2×75 mL), dried over anhydrous sodiumsulfate, filtered, and concentrated under reduced pressure. The residuewas chromatographed on a silica gel column to provide 1.60 g (58% yield)of 2-(tert-butyl) 7-(5-(trifluoromethyl)pyridin-3-yl)2,7-diazaspiro[3.5]nonane-2,7-dicarboxylate as a yellow oil. LCMS (ESI,m/z): 416 [M+H]⁺.

Step 3: Preparation of 5-(trifluoromethyl)pyridin-3-yl2-(3-(benzo[d]thiazol-2-yloxy)benzyl)-2,7-diazaspiro[3.5]nonane-7-carboxylate

The title compound was synthesized as described in Example 2, Steps 4-5,using 3-(benzo[d]thiazol-2-yloxy)benzaldehyde in Step 5 to afford 111 mg(50% yield) of 5-(trifluoromethyl)pyridin-3-yl2-(3-(benzo[d]thiazol-2-yloxy)benzyl)-2,7-diazaspiro[3.5]nonane-7-carboxylateas a colorless oil. ¹H NMR (300 MHz, Chloroform-d) δ 8.62-8.71 (m, 2H),7.66-7.76 (m, 3H), 7.30-7.48 (m, 2H), 7.32 (s, 1H), 7.12-7.24 (m, 3H),3.71 (s, 2H), 3.59 (br, 2H), 3.49 (br, 2H), 3.11-3.14 (m, 4H), 1.75-1.85(m, 4H). LCMS (ESI, m/z): 555 [M+H]⁺.

Example 8: 5-(Trifluoromethyl)pyridin-3-yl2-(4-(2-chlorophenoxy)benzyl)-2,7-diazaspiro[3.5]nonane-7-carboxylate

Step 1: Preparation of 4-(2-chlorophenoxy)benzaldehyde

A 250-mL round-bottom flask was charged with potassium carbonate (4.30g, 31.1 mmol, 2.00 equiv), 2-chlorophenol (2.00 g, 15.6 mmol, 1.00equiv), 4-fluorobenzaldehyde (1.94 g, 15.6 mmol, 1.00 equiv) andacetonitrile (50 mL) under nitrogen. The resulting solution was stirredovernight at 80° C. and quenched with water (100 mL). The mixture wasextracted with dichloromethane (3×50 mL) and the organic layers werecombined, washed with water (3×50 mL), dried over anhydrous sodiumsulfate, filtered, and concentrated under reduced pressure. The residuewas chromatographed on a silica gel column to provide 2.20 g (61% yield)of 4-(2-chlorophenoxy)benzaldehyde as a yellow oil. LCMS (ESI, m/z): 233[M+H]⁺.

Step 2: Preparation of 5-(trifluoromethyl)pyridin-3-yl2-(4-(2-chlorophenoxy)benzyl)-2,7-diazaspiro[3.5]nonane-7-carboxylate

A 50-mL round-bottom flask was charged with4-(2-chlorophenoxy)benzaldehyde (100 mg, 0.432 mmol, 1.00 equiv),5-(trifluoromethyl)pyridin-3-yl 2,7-diazaspiro[3.5]nonane-7-carboxylate(164 mg, 0.522 mmol, 1.20 equiv, prepared as described in Example 2,Steps 1-4), triethylamine (130 mg, 1.28 mmol, 3.00 equiv), and1,2-dichloroethane (10 mL). The resulting solution was stirred for 2hours at room temperature prior to the addition of sodiumtriacetoxyborohydride (228 mg, 1.08 mmol, 2.50 equiv). The reaction wasstirred overnight at room temperature and quenched with water (10 mL).The mixture was extracted with dichloromethane (3×10 mL) and the organiclayers were combined, washed with water (3×10 mL), dried over anhydroussodium sulfate, filtered, and concentrated under reduced pressure. Thecrude product was purified by preparative HPLC to afford 56.2 mg (25%yield) of 5-(trifluoromethyl)pyridin-3-yl2-(4-(2-chlorophenoxy)benzyl)-2,7-diazaspiro[3.5]nonane-7-carboxylate asa yellow oil. ¹H NMR (300 MHz, Chloroform-d) δ 8.72 (s, 1H), 8.62 (s,1H), 7.76 (s, 1H), 7.44-7.48 (m, 1H), 7.19-7.26 (m, 3H), 7.06-7.11 (m,1H), 6.90-7.00 (m, 3H), 3.50-3.64 (m, 4H), 3.49 (br, 2H), 3.10-3.11 (m,4H), 1.85-1.97 (m, 4H). LCMS (ESI, m/z): 532 [M+H]⁺.

Example 9: 5-(Trifluoromethyl)pyridin-3-yl2-(3-(2-chlorophenoxy)benzyl)-2,7-diazaspiro[3.5]nonane-7-carboxylate

Step 1: Preparation of 3-(2-chlorophenoxy)benzaldehyde

A 250-mL round-bottom flask was charged with 2-chlorophenol (1.28 g,9.96 mmol, 1.00 equiv), (3-formylphenyl)boronic acid (1.50 g, 10.0 mmol,1.00 equiv), triethylamine (5.05 g, 49.9 mmol, 5.00 equiv),1,2-dichloroethane (100 mL) and copper(II) acetate (1.82 g, 10.0 mmol,1.00 equiv). The resulting solution was stirred overnight at roomtemperature and concentrated under reduced pressure. The residue waschromatographed on a silica gel column to provide 760 mg (33% yield) of3-(2-chlorophenoxy)benzaldehyde as a yellow oil. LCMS (ESI, m/z): 233[M+H]⁺.

Step 2: Preparation of 5-(trifluoromethyl)pyridin-3-yl2-(3-(2-chlorophenoxy)benzyl)-2,7-diazaspiro[3.5]nonane-7-carboxylate

A 50-mL round-bottom flask was charged with3-(2-chlorophenoxy)benzaldehyde (100 mg, 0.432 mmol, 1.00 equiv),5-(trifluoromethyl)pyridin-3-yl 2,7-diazaspiro[3.5]nonane-7-carboxylate(164 mg, 0.522 mmol, 1.20 equiv, prepared as described in Example 2,Steps 1-4), triethylamine (130 mg, 1.28 mmol, 3.00 equiv), and1,2-dichloroethane (10 mL). The resulting solution was stirred for 2hours at room temperature prior to addition of sodiumtriacetoxyborohydride (228 mg, 1.08 mmol, 2.50 equiv). The reaction wasstirred overnight at room temperature and quenched with water (5 mL).The mixture was extracted with dichloromethane (3×10 mL) and the organiclayers were combined, washed with water (3×10 mL), dried over anhydroussodium sulfate, filtered, and concentrated under reduced pressure. Thecrude product was purified by preparative HPLC to provide 16.5 mg (7%yield) of 5-(trifluoromethyl)pyridin-3-yl2-(3-(2-chlorophenoxy)benzyl)-2,7-diazaspiro[3.5]nonane-7-carboxylate asa colorless oil. ¹H NMR (300 MHz, Chloroform-d) δ 8.72 (s, 1H), 8.62 (s,1H), 7.76 (s, 1H), 7.48-7.60 (m, 1H), 7.36-7.45 (m, 1H), 7.26-7.31 (m,1H), 7.07-7.20 (m, 2H), 7.01-7.05 (m, 1H), 6.94-6.99 (m, 1H), 6.84-6.91(m, 1H), 3.71 (s, 2H), 3.40-3.59 (m, 4H), 3.01-3.35 (m, 4H), 1.86 (br,4H). LCMS (ESI, m/z): 532 [M+H]⁺.

Example 10: 5-(Trifluoromethyl)pyridin-3-yl2-(3-(3-chlorophenoxy)benzyl)-2,7-diazaspiro[3.5]nonane-7-carboxylate

Step 1: Preparation of 3-(3-chlorophenoxy)benzaldehyde

A 500-mL round-bottom flask was charged with 3-chlorophenol (1.53 g,11.9 mmol, 1.10 equiv), potassium carbonate (11.2 g, 81.0 mmol, 8.00equiv), 3-bromobenzaldehyde (2.00 g, 10.8 mmol, 1.00 equiv), quinoline(50 mL), pyridine (100 mL) and copper(II) oxide (6.50 g, 81.2 mmol, 8.00equiv) under nitrogen. The resulting solution was stirred for 2 days at170° C., concentrated under reduced pressure and diluted with water (100mL). The mixture was extracted with ethyl acetate (3×100 mL) and theorganic layers were combined, washed with brine (3×100 mL), dried overanhydrous sodium sulfate, filtered, and concentrated under reducedpressure. The residue was chromatographed on a silica gel column toprovide 500 mg (20% yield) of 3-(3-chlorophenoxy)benzaldehyde as ayellow oil. LCMS (ESI, m/z): 233 [M+H]⁺.

Step 2: Preparation of 5-(trifluoromethyl)pyridin-3-yl2-(3-(3-chlorophenoxy)benzyl)-2,7-diazaspiro[3.5]nonane-7-carboxylate

A 50-mL round-bottom flask was charged with3-(3-chlorophenoxy)benzaldehyde (100 mg, 0.432 mmol, 0.83 equiv),5-(trifluoromethyl)pyridin-3-yl 2,7-diazaspiro[3.5]nonane-7-carboxylate(164 mg, 0.522 mmol, 1.00 equiv, prepared as described in Example 2,Steps 1-4), triethylamine (130 mg, 1.28 mmol, 2.50 equiv), and1,2-dichloroethane (10 mL). The resulting solution was stirred for 2hours at room temperature prior to addition of sodiumtriacetoxyborohydride (228 mg, 1.08 mmol, 2.50 equiv). The reaction wasstirred overnight at room temperature and quenched with water (10 mL).The mixture was extracted with dichloromethane (3×10 mL) and the organiclayers were combined, washed with water (3×10 mL), dried over anhydroussodium sulfate, filtered, and concentrated under reduced pressure. Thecrude product was purified by preparative HPLC to afford 10.8 mg (4%yield) of 5-(trifluoromethyl)pyridin-3-yl2-(3-(3-chlorophenoxy)benzyl)-2,7-diazaspiro[3.5]nonane-7-carboxylate asa colorless oil. ¹H NMR (300 MHz, Chloroform-d) δ 8.12 (s, 1H), 8.62 (s,1H), 7.76 (s, 1H), 7.31 (m, 1H), 7.28-7.31 (m, 1H), 7.00-7.12 (m, 2H),6.88-6.98 (m, 4H), 3.87 (s, 2H), 3.49-3.77 (m, 4H), 3.14-3.42 (m, 4H),1.87-1.89 (m, 4H). LCMS (ESI, m/z): 532 [M+H]⁺.

Example 11: 5-(Trifluoromethyl)pyridin-3-yl2-(3-(pyrimidin-5-yloxy)benzyl)-2,7-diazaspiro[3.5]nonane-7-carboxylate

Step 1: Preparation of 3-(pyrimidin-5-yloxy)benzaldehyde

A 250-mL round-bottom flask was charged with 5-bromopyrimidine (3.18 g,20.0 mmol, 1.00 equiv), 3-hydroxybenzaldehyde (2.44 g, 20.0 mmol, 1.00equiv), cesium carbonate (13.0 g, 40.0 mmol, 2.00 equiv), copper(I)iodide (380 mg, 2.00 mmol, 0.10 equiv), L-proline (460 mg, 4.00 mmol,0.20 equiv), and dimethyl sulfoxide (10 mL) under nitrogen. Theresulting solution was stirred overnight at 120° C. and quenched withwater (50 mL). The mixture was extracted with ethyl acetate (3×50 mL)and the organic layers were combined, washed with brine (3×50 mL), driedover anhydrous sodium sulfate, filtered, and concentrated under reducedpressure. The residue was chromatographed on a silica gel column toprovide 1.00 g (25% yield) of 3-(pyrimidin-5-yloxy)benzaldehyde as ayellow oil. LCMS (ESI, m/z): 201 [M+H]⁺.

Step 2: Preparation of 5-(trifluoromethyl)pyridin-3-yl2-(3-(pyrimidin-5-yloxy)benzyl)-2,7-diazaspiro[3.5]nonane-7-carboxylate

A 50-mL round-bottom flask was charged with3-(pyrimidin-5-yloxy)benzaldehyde (100 mg, 0.501 mmol, 1.00 equiv),5-(trifluoromethyl)pyridin-3-yl 2,7-diazaspiro[3.5]nonane-7-carboxylate(189 mg, 0.602 mmol, 1.20 equiv, prepared as described in Example 2,Steps 1-4), triethylamine (151 mg, 1.49 mmol, 3.00 equiv), and1,2-dichloroethane (10 mL). The resulting solution was stirred for 2hours at room temperature prior to addition of sodiumtriacetoxyborohydride (265 mg, 1.25 mmol, 2.50 equiv). The resultingsolution was stirred overnight at room temperature and quenched withwater (10 mL). The mixture was extracted with dichloromethane (3×10 mL)and the organic layers were combined, washed with water (3×10 mL), driedover anhydrous sodium sulfate, filtered, and concentrated under reducedpressure. The crude product was purified by preparative HPLC to provide36.5 mg (15% yield) of 5-(trifluoromethyl)pyridin-3-yl2-(3-(pyrimidin-5-yloxy)benzyl)-2,7-diazaspiro[3.5]nonane-7-carboxylateas a gray semi-solid. ¹H NMR (300 MHz, Chloroform-d) δ 8.98 (s, 1H),8.72 (s, 1H), 8.62 (s, 1H), 8.48 (s, 2H), 7.77 (s, 1H), 7.34-7.39 (m,1H), 7.15-7.18 (m, 1H), 7.05 (s, 1H), 6.95-6.98 (m, 1H), 3.70 (s, 2H),3.49-3.60 (m, 4H), 3.14 (br, 4H), 1.87 (br, 4H). LCMS (ESI, m/z): 500[M+H]⁺.

Example 12: 5-(Trifluoromethyl)pyridin-3-yl2-(3-(((6-(trifluoromethyl)pyridin-2-yl)oxy)benzyl)-2,7-diazaspiro[3.5]nonane-7-carboxylate

Step 1: Preparation of3-((6-(trifluoromethyl)pyridin-2-yl)oxy)benzaldehyde

A 100-mL round-bottom flask was charged with2-fluoro-6-(trifluoromethyl)pyridine (0.330 g, 2.00 mmol, 1.00 equiv),3-hydroxybenzaldehyde (0.244 g, 2.00 mmol, 1.00 equiv), cesium carbonate(1.30 g, 4.00 mmol, 2.00 equiv), and DMF (15 mL) under nitrogen. Theresulting solution was stirred overnight at 120° C. and quenched withwater (40 mL). The mixture was extracted with dichloromethane (3×50 mL)and the organic layers were combined, washed with water (3×20 mL), driedover anhydrous sodium sulfate, filtered, and concentrated under reducedpressure. The residue was chromatographed on a silica gel column toprovide 0.438 g (82% yield) of3-((6-(trifluoromethyl)pyridin-2-yl)oxy)benzaldehyde as a yellow solid.LCMS (ESI, m/z): 268 [M+H]⁺.

Step 2: Preparation of 5-(trifluoromethyl)pyridin-3-yl2-(3-(((6-(trifluoromethyl)pyridin-2-yl)oxy)benzyl)-2,7-diazaspiro[3.5]nonane-7-carboxylate

A 50-mL round-bottom flask was charged with3-((6-(trifluoromethyl)pyridin-2-yl)oxy)benzaldehyde (160 mg, 0.601mmol, 1.00 equiv), 5-(trifluoromethyl)pyridin-3-yl2,7-diazaspiro[3.5]nonane-7-carboxylate (189 mg, 0.601 mmol, 1.00 equiv,prepared as described in Example 2, Steps 1-4), triethylamine (121 mg,1.20 mmol, 2.00 equiv), and 1,2-dichloroethane (10 mL). The resultingsolution was stirred for 2 hours at room temperature prior to additionof sodium triacetoxyborohydride (382 mg, 1.80 mmol, 3.00 equiv). Thereaction was stirred overnight at room temperature and quenched withwater (40 mL). The mixture was extracted with dichloromethane (3×50 mL)and the organic layers were combined, washed with water (3×20 mL), driedover anhydrous sodium sulfate, filtered, and concentrated under reducedpressure. The crude product was purified by preparative HPLC to provide86.4 mg (25% yield) of 5-(trifluoromethyl)pyridin-3-yl2-(3-((6-(trifluoromethyl)pyridin-2-yl)oxy)benzyl)-2,7-diazaspiro[3.5]nonane-7-carboxylateas a colorless oil. ¹H NMR (300 MHz, Chloroform-d) δ 8.50-8.80 (m, 2H),7.68-7.95 (m, 2H), 7.30-7.50 (m, 2H), 7.10-7.25 (m, 2H), 6.98-7.10 (m,2H), 3.68 (s, 2H), 3.37-3.63 (m, 4H), 2.92-3.23 (m, 4H), 1.72-1.92 (d,J=3.0 Hz, 4H). LCMS (ESI, m/z): 567 [M+H]⁺.

Example 13: 5-(Trifluoromethyl)pyridin-3-yl2-(2-chloro-3-(2-chlorophenoxy)benzyl)-2,7-diazaspiro[3.5]nonane-7-carboxylate

Step 1: Preparation of bis(2-chlorophenyl)iodonium tetrafluoroborate

A 100-mL round-bottom flask was charged with 3-chloroperoxybenzoic acid(1.20 g, 6.94 mmol, 1.12 equiv), 1-chloro-2-iodobenzene (1.48 mg, 6.20mmol, 1.00 equiv), boron trifluoride etherate (2.18 g, 15.5 mmol, 2.50equiv), and dichloromethane (30 mL). The resulting solution was stirredat room temperature for 30 minutes, and cooled to 0° C. prior toaddition of (2-chlorophenyl)boronic acid (1.08 g, 6.91 mmol, 1.12equiv). The reaction was stirred for 30 minutes at room temperature andquenched with water (40 mL). The mixture was extracted withdichloromethane (3×50 mL) and the organic layers were combined, washedwith water (3×20 mL), dried over anhydrous sodium sulfate, filtered, andconcentrated under reduced pressure. The residue was chromatographed ona silica gel column to provide 1.36 g (50% yield) ofbis(2-chlorophenyl)iodonium tetrafluoroborate as a yellow oil. LCMS(ESI, m/z): 349 [M−BF4]⁺.

Step 2: Preparation of 2-chloro-3-(2-chlorophenoxy)benzaldehyde

A 100-mL round-bottom flask was charged with2-chloro-3-hydroxybenzaldehyde (0.366 g, 2.34 mmol, 1.00 equiv),potassium tert-butoxide (0.289 g, 2.58 mmol, 1.10 equiv),bis(2-chlorophenyl)iodonium tetrafluoroborate (1.23 g, 2.82 mmol, 1.20equiv), and tetrahydrofuran (10 mL). The resulting solution was stirredovernight at 40° C. and quenched with water (40 mL). The mixture wasextracted with dichloromethane (3×30 mL) and the organic layers werecombined, washed with water (3×10 mL), dried over anhydrous sodiumsulfate, filtered, and concentrated under reduced pressure to provide0.481 g of 2-chloro-3-(2-chlorophenoxy)benzaldehyde as a yellow solid.LCMS (ESI, m/z): 267 [M+H]⁺.

Step 3: Preparation of 5-(trifluoromethyl)pyridin-3-yl2-(2-chloro-3-(2-chlorophenoxy)benzyl)-2,7-diazaspiro[3.5]nonane-7-carboxylate

A 50-mL round-bottom flask was charged with2-chloro-3-(2-chlorophenoxy)benzaldehyde (120 mg, 0.451 mmol, 1.00equiv), 5-(trifluoromethyl)pyridin-3-yl2,7-diazaspiro[3.5]nonane-7-carboxylate (141 mg, 0.451 mmol, 1.00 equiv,prepared as described by Example 2, Steps 1-4), triethylamine (91.1 mg,0.902 mmol, 2.00 equiv), and 1,2-dichloroethane (10 mL). The resultingsolution was stirred for 2 hours at room temperature prior to additionof sodium triacetoxyborohydride (286 mg, 1.35 mmol, 3.00 equiv). Thereaction was stirred overnight at room temperature and quenched withwater (40 mL). The mixture was extracted with dichloromethane (3×50 mL)and the organic layers were combined, washed with water (3×20 mL), driedover anhydrous sodium sulfate, filtered, and concentrated under reducedpressure. The crude product was purified by preparative HPLC to provide52.8 mg (21% yield) of 5-(trifluoromethyl)pyridin-3-yl2-(2-chloro-3-(2-chlorophenoxy)benzyl)-2,7-diazaspiro[3.5]nonane-7-carboxylateas a white solid. ¹H NMR (400 MHz, Chloroform-d) δ 8.72 (s, 1H), 8.63(d, J=2.4 Hz, 1H), 7.78 (s, 1H), 7.48 (m, 1H), 7.14-7.26 (m, 3H),7.01-7.14 (m, 1H), 6.81-6.93 (m, 1H), 6.68-6.81 (m, 1H), 3.84 (s, 2H),3.57-3.70 (m, 2H), 3.45-3.57 (m, 2H), 3.22 (s, 4H), 1.81-2.00 (m, 4H).LCMS (ESI, m/z): 566 [M+H]⁺.

Example 14: 5-(Trifluoromethyl)pyridin-3-yl2-(2,4-dichloro-3-phenoxybenzyl)-2,7-diazaspiro[3.5]nonane-7-carboxylate

Step 1: Preparation of 2,4-dichloro-3-phenoxybenzaldehyde

A 100-mL round-bottom flask was charged with2,4-dichloro-3-hydroxybenzaldehyde (0.380 g, 1.99 mmol, 1.00 equiv),potassium tert-butoxide (0.246 g, 2.19 mmol, 1.10 equiv),diphenyliodonium hexafluorophosphate (1.02 g, 2.39 mmol, 1.20 equiv),and tetrahydrofuran (10 mL). The resulting solution was stirredovernight at 40° C. and quenched with water (40 mL). The mixture wasextracted with dichloromethane (3×30 mL) and the organic layers werecombined, washed with water (3×10 mL), dried over anhydrous sodiumsulfate, filtered, and concentrated under reduced pressure to provide0.380 g of 2,4-dichloro-3-phenoxybenzaldehyde as a yellow solid. LCMS(ESI, m/z): 267 [M+H]⁺.

Step 2: Preparation of 5-(trifluoromethyl)pyridin-3-yl2-(2,4-dichloro-3-phenoxybenzyl)-2,7-diazaspiro[3.5]nonane-7-carboxylate

A 50-mL round-bottom flask was charged with2,4-dichloro-3-phenoxybenzaldehyde (134 mg, 0.500 mmol, 1.00 equiv),5-(trifluoromethyl)pyridin-3-yl 2,7-diazaspiro[3.5]nonane-7-carboxylate(158 mg, 0.500 mmol, 1.00 equiv, prepared as described in Example 2,Steps 1-4), triethylamine (152 mg, 1.50 mmol, 3.00 equiv), and1,2-dichloroethane (20 mL). The resulting solution was stirred for 2hours at room temperature prior to addition of sodiumtriacetoxyborohydride (318 mg, 1.50 mmol, 3.00 equiv). The reaction wasstirred overnight at room temperature and quenched with water (40 mL).The mixture was extracted with dichloromethane (3×50 mL) and the organiclayers were combined, washed with water (3×20 mL), dried over anhydroussodium sulfate, filtered, and concentrated under reduced pressure. Thecrude product was purified by preparative HPLC to afford 60.3 mg (21%yield) of 5-(trifluoromethyl)pyridin-3-yl2-(2,4-dichloro-3-phenoxybenzyl)-2,7-diazaspiro[3.5]nonane-7-carboxylateas a white solid. ¹H NMR (400 MHz, Chloroform-d) δ 8.74 (s, 1H),8.40-8.68 (d, J=2.3 Hz, 1H), 7.78 (s, 1H), 7.28-7.48 (m, 4H), 6.99-7.15(m, 1H), 6.73-6.93 (m, 2H), 3.80 (s, 2H), 3.49-3.68 (m, 4H), 3.20 (s,4H), 1.90 (s, 4H). LCMS (ESI, m/z): 566 [M+H]⁺.

Example 15: 5-(Methylsulfonamido)pyridin-3-yl4-(4-chloro-3-isopropoxybenzyl)piperazine-1-carboxylate

Step 1: Preparation of 5-(methylsulfonamido)pyridin-3-yl4-(4-chloro-3-isopropoxybenzyl)piperazine-1-carboxylate

A 50-mL round-bottom flask was charged with 5-aminopyridin-3-yl4-(4-chloro-3-isopropoxybenzyl)piperazine-1-carboxylate (83.0 mg, 0.200mmol, 1.00 equiv, prepared as described in Example 6, Steps 1-5),triethylamine (63.6 mg, 0.630 mmol, 3.00 equiv) and dichloromethane (5mL). Methylsulfonyl chloride (36.2 mg, 0.310 mmol, 1.50 equiv) was addedat 0° C. The resulting solution was stirred for 2 hours at roomtemperature and concentrated under reduced pressure. The crude productwas purified by preparative HPLC to provide 83.4 mg (84% yield) of5-(methylsulfonamido)pyridin-3-yl4-(4-chloro-3-isopropoxybenzyl)piperazine-1-carboxylate as a yellowsolid. ¹H NMR (300 MHz, Chloroform-d) δ 8.14-8.35 (m, 2H), 7.87-8.14 (m,1H), 7.52-7.67 (m, 1H), 7.26-7.37 (m, 1H), 6.98 (s, 1H), 6.73-6.91 (m,1H), 4.45-4.67 (m, 1H), 3.42-3.78 (m, 6H), 3.04 (s, 3H), 2.35-2.57 (m,4H), 1.30-1.47 (m, 6H). LCMS (ESI, m/z): 483 [M+H]⁺.

Example 16: 5-Carbamoylpyridin-3-yl4-(3-carbamoyl-4-chlorobenzyl)piperazine-1-carboxylate

Step 1: Preparation of 2-chloro-5-formylbenzamide

A 50-mL round-bottom flask was charged with2-chloro-5-formylbenzonitrile (500 mg, 3.00 mmol, 1.00 equiv) andsulfuric acid (10 mL). The resulting solution was stirred for 2 hours at110° C. and poured into ice-water (20 mL). The mixture was extractedwith ethyl acetate (3×30 mL), washed with water (3×10 mL), dried overanhydrous sodium sulfate, filtered, and concentrated under reducedpressure to provide 430 mg (78% yield) of 2-chloro-5-formylbenzamide asa yellow solid.

Step 2: Preparation of 5-carbamoylpyridin-3-yl4-(3-carbamoyl-4-chlorobenzyl)piperazine-1-carboxylate

A 40-mL vial was charged with 5-carbamoylpyridin-3-ylpiperazine-1-carboxylate (100 mg, 0.400 mmol, 1.00 equiv),2-chloro-5-formylbenzamide (135 mg, 0.740 mmol, 1.00 equiv) anddichloromethane (10 mL). The resulting solution was stirred for 1 hourat room temperature prior to addition of sodium triacetoxyborohydride(228 mg, 1.08 mmol, 2.00 equiv). The reaction was stirred overnight atroom temperature and quenched with water (10 mL). The mixture wasextracted with dichloromethane (3×20 mL) and the organic layers werecombined, washed with water (3×10 mL), dried over anhydrous sodiumsulfate, filtered, and concentrated under reduced pressure. The crudeproduct was purified by preparative HPLC to provide 61.4 mg (37% yield)of 5-carbamoylpyridin-3-yl4-(3-carbamoyl-4-chlorobenzyl)piperazine-1-carboxylate as a white solid.¹H NMR (300 MHz, Methanol-d4) δ 8.82-8.99 (m, 1H), 8.50-8.65 (m, 1H),8.03-8.14 (m, 1H), 7.48-7.60 (m, 1H), 7.38-7.48 (m, 2H), 3.67-3.85 (m,2H), 3.51-3.67 (m, 4H), 2.48-2.67 (m, 4H). LCMS (ESI, m/z): 418 [M+H]⁺.

Example 17: 5-Carbamoylpyridin-3-yl4-(4-(2-methylpyrrolidin-1-yl)-2-(trifluoromethoxy)benzyl)piperazine-1-carboxylate

Step 1: Preparation of4-(2-methylpyrrolidin-1-yl)-2-(trifluoromethoxy)benzaldehyde

A 50-mL round-bottom flask was charged with4-bromo-2-(trifluoromethoxy)benzaldehyde (0.500 g, 1.86 mmol, 1.00equiv), cesium carbonate (1.82 g, 5.59 mmol, 3.00 equiv),2-methylpyrrolidine (0.367 g, 4.31 mmol, 2.00 equiv),2,2′-bis(diphenylphosphino)-1,1′-binaphthyl (0.116 g, 0.190 mmol, 0.10equiv), tris(dibenzylideneacetone)dipalladium (0.100 g, 0.110 mmol, 0.05equiv), and toluene (10 mL) under nitrogen. The resulting solution wasstirred overnight at 80° C. under nitrogen atmosphere and quenched withwater (20 mL). The mixture was extracted with ethyl acetate (3×30 mL)and the organic layers were combined, washed with water (3×10 mL), driedover anhydrous sodium sulfate, filtered, and concentrated under reducedpressure. The residue was chromatographed on a silica gel column toprovide 0.300 g (59% yield) of4-(2-methylpyrrolidin-1-yl)-2-(trifluoromethoxy)benzaldehyde as a whiteoil. LCMS (ESI, m/z): 274 [M+H]⁺.

Step 2: Preparation of tert-butyl4-(chlorocarbonyl)piperazine-1-carboxylate

A 100-mL round-bottom flask was charged with tert-butylpiperazine-1-carboxylate (2.86 g, 15.4 mmol, 1.00 equiv), triphosgene(2.29 g, 7.71 mmol, 0.50 equiv) and dichloromethane (20 mL). DIPEA (7.95g, 61.5 mmol, 4.00 equiv) was added at 0° C. and the resulting solutionwas stirred for 2 hours at room temperature. The reaction was quenchedwith water (20 mL), extracted with dichloromethane (3×30 mL), and theorganic layers were combined, washed with water (3×10 mL), dried overanhydrous sodium sulfate, filtered, and concentrated under reducedpressure to provide 3.82 g of tert-butyl4-(chlorocarbonyl)piperazine-1-carboxylate as a yellow solid.

Step 3: Preparation of 1-(tert-butyl) 4-(5-carbamoylpyridin-3-yl)piperazine-1,4-dicarboxylate

A 50-mL round-bottom flask was charged with5-hydroxypyridine-3-carboxamide (276 mg, 2.00 mmol, 1.00 equiv),tert-butyl 4-(chlorocarbonyl)piperazine-1-carboxylate (598 mg, 2.40mmol, 1.20 equiv), 4-dimethylaminopyridine (48.8 mg, 0.400 mmol, 0.20equiv), DIPEA (774 mg, 5.99 mmol, 3.00 equiv) and tetrahydrofuran (10mL). The resulting solution was stirred overnight at 60° C. and quenchedwith water (20 mL). The mixture was extracted with ethyl acetate (3×30mL) and the organic layers were combined, washed with water (3×10 mL),dried over anhydrous sodium sulfate, filtered, and concentrated underreduced pressure. The residue was chromatographed on a silica gel columnto provide 437 mg (62% yield) of 1-(tert-butyl)4-(5-carbamoylpyridin-3-yl) piperazine-1,4-dicarboxylate as a white oil.LCMS (ESI, m/z): 351 [M+H]⁺.

Step 4: Preparation of 5-carbamoylpyridin-3-yl piperazine-1-carboxylate

A 50-mL round-bottom flask was charged with 1-(tert-butyl)4-(5-carbamoylpyridin-3-yl) piperazine-1,4-dicarboxylate (200 mg, 0.570mmol, 1.00 equiv), trifluoroacetic acid (1 mL) and dichloromethane (4mL). The resulting solution was stirred for 2 hours at room temperatureand concentrated under reduced pressure to provide 143 mg of5-carbamoylpyridin-3-yl piperazine-1-carboxylate as a white oil. LCMS(ESI, m/z): 251 [M+H]⁺.

Step 5: Preparation of 5-carbamoylpyridin-3-yl4-(4-(2-methylpyrrolidin-1-yl)-2-(trifluoromethoxy)benzyl)piperazine-1-carboxylate

A 50-mL round-bottom flask was charged with 5-carbamoylpyridin-3-ylpiperazine-1-carboxylate (107 mg, 0.430 mmol, 1.00 equiv),4-(2-methylpyrrolidin-1-yl)-2-(trifluoromethoxy)benzaldehyde (117 mg,0.430 mmol, 1.00 equiv) and 1,2-dichloroethane (5 mL). The resultingsolution was stirred for 1 hour at room temperature prior to addition ofsodium triacetoxyborohydride (182 mg, 0.860 mmol, 2.00 equiv). Thereaction was stirred overnight at room temperature and quenched withwater (10 mL). The mixture was extracted with dichloromethane (3×30 mL)and the organic layers were combined, washed with water (3×10 mL), driedover anhydrous sodium sulfate, filtered, and concentrated under reducedpressure. The crude product was purified by preparative HPLC to provide14.5 mg (8% yield) of 5-carbamoylpyridin-3-yl4-(4-(2-methylpyrrolidin-1-yl)-2-(trifluoromethoxy)benzyl)piperazine-1-carboxylateas a white solid. ¹H NMR (300 MHz, Chloroform-d) δ 8.75-8.87 (m, 1H),8.50-8.61 (m, 1H), 7.92-7.98 (m, 1H), 7.16-7.25 (m, 1H), 6.43-6.50 (m,1H), 6.38 (s, 1H), 6.05-6.31 (m, 1H), 5.59-5.95 (m, 1H), 3.34-3.92 (m,8H), 3.05-3.22 (m, 1H), 2.50 (s, 4H), 1.91-2.17 (m, 3H), 3.78-2.87 (m,1H), 1.10-1.24 (m, 3H). LCMS (ESI, m/z): 508 [M+H]⁺.

Example 18: 5-Carbamoylpyridin-3-yl4-(4-isopropoxy-2-(trifluoromethoxy)benzyl)piperazine-1-carboxylate

Step 1: Preparation of tert-butyl4-(4-bromo-2-(trifluoromethoxy)benzyl)piperazine-1-carboxylate

A 100-mL round-bottom flask was charged with4-bromo-2-(trifluoromethoxy)benzaldehyde (1.08 g, 4.00 mmol, 1.00equiv), tert-butyl piperazine-1-carboxylate (0.823 g, 4.42 mmol, 1.10equiv) and 1,2-dichloroethane (50 mL). The resulting solution wasstirred for 1 hour at room temperature prior to addition of sodiumtriacetoxyborohydride (1.70 g, 8.00 mmol, 2.00 equiv). The resultingsolution was stirred overnight at room temperature and quenched withwater (30 mL). The mixture was extracted with dichloromethane (3×50 mL)and the organic layers were combined, washed with water (3×30 mL), driedover anhydrous sodium sulfate, filtered, and concentrated under reducedpressure. The residue was chromatographed on a silica gel column toprovide 0.980 g (55.6% yield) of tert-butyl4-(4-bromo-2-(trifluoromethoxy)benzyl)piperazine-1-carboxylate as awhite solid. LCMS (ESI, m/z): 439 [M+H]⁺.

Step 2: Preparation of tert-butyl4-(4-hydroxy-2-(trifluoromethoxy)benzyl)piperazine-1-carboxylate

A 40-mL vial was charged with tert-butyl4-(4-bromo-2-(trifluoromethoxy)benzyl)piperazine-1-carboxylate (880 mg,2.00 mmol, 1.00 equiv), tris(dibenzylideneacetone)dipalladium (183 mg,0.200 mmol, 0.10 equiv),2-di-tert-butylphosphino-2′,4′,6′-triisopropylbiphenyl (85.1 mg, 0.200mmol, 0.10 equiv), potassium hydroxide (449 mg, 8.01 mmol, 4.00 equiv),water (2 mL) and 1,4-dioxane (8 mL) under nitrogen atmosphere. Theresulting solution was stirred for 12 hours at 100° C. and quenched withwater (10 mL). The mixture was extracted with dichloromethane (3×30 mL)and the organic layers were combined, washed with water (3×20 mL), driedover anhydrous sodium sulfate, filtered, and concentrated under reducedpressure. The residue was chromatographed on a silica gel column toprovide 661 mg (87.7% yield) of tert-butyl4-(4-hydroxy-2-(trifluoromethoxy)benzyl)piperazine-1-carboxylate as awhite solid. LCMS (ESI, m/z): 377 [M+H]⁺.

Step 3: Preparation of tert-butyl4-(4-isopropoxy-2-(trifluoromethoxy)benzyl)piperazine-1-carboxylate

A 40-mL vial was charged with tert-butyl4-(4-hydroxy-2-(trifluoromethoxy)benzyl)piperazine-1-carboxylate (0.500g, 1.33 mmol, 1.00 equiv), 2-iodopropane (0.248 g, 1.46 mmol, 1.10equiv), cesium carbonate (1.30 g, 3.98 mmol, 3.00 equiv) and dimethylformamide (15 mL). The reaction was stirred overnight at 60° C. anddiluted with water (5 mL). The resulting solution was extracted withethyl acetate (3×30 mL) and the organic layers were combined, washedwith brine (2×20 mL), dried over anhydrous sodium sulfate, filtered, andconcentrated under reduced pressure. The residue was chromatographed ona silica gel column to provide 420 mg (76% yield) of tert-butyl4-(4-isopropoxy-2-(trifluoromethoxy)benzyl)piperazine-1-carboxylate as ayellow oil. LCMS (ESI, m/z): 419 [M+H]⁺.

Step 4: Preparation of4-(4-isopropoxy-2-(trifluoromethoxy)benzyl)piperazine-1-carbonylchloride

A 40-mL vial was charged with tert-butyl4-(4-isopropoxy-2-(trifluoromethoxy)benzyl)piperazine-1-carboxylate (200mg, 0.480 mmol, 1.00 equiv), dichloromethane (10 mL) and trifluoroaceticacid (2 mL). The resulting solution was stirred for 3 hours at roomtemperature and concentrated under reduced pressure to provide 152 mg of1-(4-isopropoxy-2-(trifluoromethoxy)benzyl)piperazine as a white solid(LCMS (ESI, m/z): 319 [M+H]⁺). This crude product was transferred to a40-mL vial to which triphosgene (71.3 mg, 0.240 mmol, 0.50 equiv) anddichloromethane (15 mL) were added. DIPEA (278 mg, 2.16 mmol, 4.50equiv) was added dropwise at 0° C. The reaction was stirred for 2 hoursat room temperature and diluted with water (5 mL). The mixture wasextracted with dichloromethane (3×5 mL) and the organic layers werecombined, washed with brine (3×5 mL) and dried over anhydrous sodiumsulfate, filtered, and concentrated under reduced pressure to provide182 mg of4-(4-isopropoxy-2-(trifluoromethoxy)benzyl)piperazine-1-carbonylchloride as a yellow solid.

Step 5: Preparation of 5-carbamoylpyridin-3-yl4-(4-isopropoxy-2-(trifluoromethoxy)benzyl)piperazine-1-carboxylate

A 40-mL vial was charged with4-(4-isopropoxy-2-(trifluoromethoxy)benzyl)piperazine-1-carbonylchloride (182 mg, 0.480 mmol, 1.00 equiv),5-hydroxypyridine-3-carboxamide (66.0 mg, 0.480 mmol, 1.00 equiv),4-dimethylaminopyridine (11.7 mg, 0.100 mmol, 0.20 equiv), DIPEA (124mg, 0.960 mmol, 2.00 equiv) and tetrahydrofuran (15 mL). The resultingsolution was stirred overnight at 60° C. and quenched with water (20mL). The mixture was extracted with dichloromethane (3×30 mL) and theorganic layers were combined, washed with water (3×10 mL), dried overanhydrous sodium sulfate, filtered, and concentrated under reducedpressure. The crude product was purified by preparative HPLC to afford60.3 mg (26% yield) of 5-carbamoylpyridin-3-yl4-(4-isopropoxy-2-(trifluoromethoxy)benzyl)piperazine-1-carboxylate as awhite solid. ¹H NMR (300 MHz, Methanol-d4) δ 8.89-8.90 (m, 1H),8.56-8.57 (m, 1H), 8.08-8.10 (m, 1H), 7.45-7.49 (m, 1H), 6.92-6.95 (m,1H), 6.81-6.82 (m, 1H), 4.59-4.67 (m, 1H), 3.75 (br, 2H), 3.58 (br, 4H),2.56 (br, 4H), 1.33-1.35 (m, 6H). LCMS (ESI, m/z): 483 [M+H]⁺.

Example 19: 5-Cyanopyridin-3-yl(R)-2-methyl-4-04-(trifluoromethyl)pyridin-3-yl)methyl)piperazine-1-carboxylate

Step 1: Preparation of tert-butyl(R)-4-(chlorocarbonyl)-3-methylpiperazine-1-carboxylate

A 100-mL round-bottom flask was charged with triphosgene (0.743 g, 2.50mmol, 0.50 equiv), tert-butyl (R)-3-methylpiperazine-1-carboxylate (1.00g, 5.00 mmol, 1.00 equiv), and dichloromethane (10 mL). DIPEA (1.94 g,15.0 mmol, 3.00 equiv) was added at 0° C. The reaction was stirred for 3hours at room temperature and quenched with water (80 mL). The mixturewas extracted with dichloromethane (2×100 mL) and the organic layerswere combined, washed with brine (2×80 mL), dried over anhydrous sodiumsulfate, filtered, and concentrated under reduced pressure to provide1.40 g of tert-butyl(R)-4-(chlorocarbonyl)-3-methylpiperazine-1-carboxylate as a yellow oil.LCMS (ESI, m/z): 263 [M+H]⁺.

Step 2: Preparation of 4-(tert-butyl) 1-(5-cyanopyridin-3-yl)(R)-2-methylpiperazine-1,4-dicarboxylate

A 50-mL round-bottom flask was charged with tert-butyl(R)-4-(chlorocarbonyl)-3-methylpiperazine-1-carboxylate (1.31 g, 5.00mmol, 1.00 equiv), 5-hydroxypyridine-3-carbonitrile (0.720 g, 6.00 mmol,1.20 equiv), DIPEA (1.94 g, 15.0 mmol, 3.00 equiv),4-dimethylaminopyridine (0.122 g, 1.00 mmol, 0.20 equiv), andtetrahydrofuran (10 mL). The reaction was stirred overnight at 60° C.and quenched with water (50 mL). The resulting solution was extractedwith dichloromethane (2×80 mL) and the organic layers were combined,washed with brine (2×50 mL), dried over anhydrous sodium sulfate,filtered, and concentrated under reduced pressure. The residue waschromatographed on a silica gel column to provide 1.30 g (75% yield) of4-(tert-butyl) 1-(5-cyanopyridin-3-yl)(R)-2-methylpiperazine-1,4-dicarboxylate as a yellow solid. LCMS (ESI,m/z): 347 [M+H]⁺.

Step 3: Preparation of 5-cyanopyridin-3-yl(R)-2-methylpiperazine-1-carboxylate

A 50-mL round-bottom flask was charged with 4-(tert-butyl)1-(5-cyanopyridin-3-yl) (R)-2-methylpiperazine-1,4-dicarboxylate (750mg, 2.17 mmol, 1.00 equiv), dichloromethane (10 mL), and trifluoroaceticacid (2 mL). The resulting solution was stirred for 3 hours at roomtemperature and concentrated under reduced pressure to provide 800 mg of5-cyanopyridin-3-yl (R)-2-methylpiperazine-1-carboxylate as a yellowoil. LCMS (ESI, m/z): 247 [M+H]⁺.

Step 4: Preparation of 5-cyanopyridin-3-yl(R)-2-methyl-4-((4-(trifluoromethyl)pyridin-3-yl)methyl)piperazine-1-carboxylate

A 50-mL round-bottom flask was charged with 5-cyanopyridin-3-yl(R)-2-methylpiperazine-1-carboxylate (179 mg, 0.727 mmol, 1.20 equiv),4-(trifluoromethyl)pyridine-3-carbaldehyde (106 mg, 0.606 mmol, 1.00equiv), triethylamine (184 mg, 1.82 mmol, 3.00 equiv), and1,2-dichloroethane (10 mL). The mixture was stirred for 1 hour at roomtemperature prior to addition of sodium triacetoxyborohydride (386 mg,1.82 mmol, 3.00 equiv). The reaction was stirred overnight at roomtemperature and quenched with water (30 mL). The resulting solution wasextracted with dichloromethane (2×50 mL) and the organic layers werecombined, washed with brine (2×30 mL), dried over anhydrous sodiumsulfate, filtered, and concentrated under reduced pressure. The crudeproduct (300 mg) was purified by preparative HPLC to afford 94.9 mg (39%yield) of 5-cyanopyridin-3-yl(R)-2-methyl-4-((4-(trifluoromethyl)pyridin-3-yl)methyl)piperazine-1-carboxylateas a yellow oil. ¹H NMR (300 MHz, Chloroform-d) δ 9.02 (s, 1H),8.71-8.73 (m, 2H), 8.64 (s, 1H), 7.84 (s, 1H), 7.54 (d, J=5.1 Hz, 1H),4.41 (br, 1H), 3.99-4.03 (m, 1H), 3.73 (s, 2H), 3.48 (br, 1H), 2.84-2.87(m, 1H), 2.69-2.73 (m, 1H), 2.42-2.47 (m, 1H), 2.01-2.31 (m, 1H),1.41-1.42 (m, 3H). LCMS (ESI, m/z): 406 [M+H]⁺.

Example 20: 5-Carbamoylpyridin-3-yl(R)-4-(3-fluoro-5-(trifluoromethyl)benzyl)-2-methylpiperazine-1-carboxylate

Step 1: Preparation of tert-butyl(R)-4-(3-fluoro-5-(trifluoromethyl)benzyl)-2-methylpiperazine-1-carboxylate

A 100-mL round-bottom flask was charged with3-fluoro-5-(trifluoromethyl)benzaldehyde (2.00 g, 10.4 mmol, 1.00equiv), tert-butyl (R)-2-methylpiperazine-1-carboxylate (2.50 g, 12.5mmol, 1.20 equiv), triethylamine (3.16 g, 31.2 mmol, 3.00 equiv), and1,2-dichloroethane (20 mL). The mixture was stirred for 30 minutes atroom temperature prior to addition of sodium triacetoxyborohydride (6.63g, 31.2 mmol, 3.00 equiv). The reaction was stirred overnight at roomtemperature and quenched with water (20 mL). The resulting solution wasextracted with dichloromethane (3×30 mL) and the organic layers werecombined, washed with brine (2×10 mL), dried over anhydrous sodiumsulfate, filtered, and concentrated under reduced pressure. The residuewas chromatographed on a silica gel column to provide 3.00 g (77% yield)of tert-butyl(R)-4-(3-fluoro-5-(trifluoromethyl)benzyl)-2-methylpiperazine-1-carboxylateas a colorless oil. LCMS (ESI, m/z): 377 [M+H]⁺.

Step 2: Preparation of(R)-1-(3-fluoro-5-(trifluoromethyl)benzyl)-3-methylpiperazine

A 100-mL round-bottom flask was charged with tert-butyl(R)-4-(3-fluoro-5-(trifluoromethyl)benzyl)-2-methylpiperazine-1-carboxylate(2.00 g, 5.31 mmol, 1.00 equiv), dichloromethane (20 mL), andtrifluoroacetic acid (5 mL). The resulting solution was stirred for 2hours at room temperature and concentrated under reduced pressure. Thecrude product was dissolved in saturated NaHCO₃ solution (20 mL) andextracted with dichloromethane (3×60 mL). The organic layers werecombined, washed with brine (2×20 mL), dried over anhydrous sodiumsulfate, filtered, and concentrated under reduced pressure to provide1.87 g of (R)-1-(3-fluoro-5-(trifluoromethyl)benzyl)-3-methylpiperazineas a light yellow oil. LCMS (ESI, m/z): 277 [M+H]⁺.

Step 3: Preparation of(R)-4-(3-fluoro-5-(trifluoromethyl)benzyl)-2-methylpiperazine-1-carbonylchloride

A 50-mL round-bottom flask was charged with triphosgene (646 mg, 2.18mmol, 0.50 equiv), dichloromethane (10 mL),(R)-1-(3-fluoro-5-(trifluoromethyl)benzyl)-3-methylpiperazine (1.20 g,4.34 mmol, 1.00 equiv). DIPEA (2.24 g, 17.4 mmol, 4.00 equiv) was addeddropwise 0° C. The reaction was stirred for 2 hours at room temperatureand quenched with water (10 mL). The resulting solution was extractedwith dichloromethane (3×20 mL) and the organic layers were combined,washed with brine (2×10 mL), dried over anhydrous sodium sulfate,filtered, and concentrated under reduced pressure to provide 1.40 g (95%yield) of(R)-4-(3-fluoro-5-(trifluoromethyl)benzyl)-2-methylpiperazine-1-carbonylchloride as a yellow oil. LCMS (ESI, m/z): 339 [M+H]⁺.

Step 4: Preparation of 5-carbamoylpyridin-3-yl(R)-4-(3-fluoro-5-(trifluoromethyl)benzyl)-2-methylpiperazine-1-carboxylate

A 25-mL round-bottom flask was charged with(R)-4-(3-fluoro-5-(trifluoromethyl)benzyl)-2-methylpiperazine-1-carbonylchloride (350 mg, 1.03 mmol, 1.00 equiv),5-hydroxypyridine-3-carboxamide (171 mg, 1.24 mmol, 1.20 equiv),4-dimethylaminopyridine (25.2 mg, 0.206 mmol, 0.20 equiv), DIPEA (400mg, 3.10 mmol, 3.00 equiv), and tetrahydrofuran (5 mL). The reaction wasstirred overnight at 60° C. and quenched with water (10 mL). Theresulting solution was extracted with dichloromethane (3×20 mL) and theorganic layers were combined, washed with brine (2×10 mL), dried overanhydrous sodium sulfate, filtered, and concentrated under reducedpressure. The crude product (400 mg) was purified by preparative HPLC toprovide 96.9 mg (21% yield) of 5-carbamoylpyridin-3-yl(R)-4-(3-fluoro-5-(trifluoromethyl)benzyl)-2-methylpiperazine-1-carboxylateas an off-white solid. ¹H NMR (300 MHz, Chloroform-d) δ 8.83 (d, J=1.5Hz, 1H), 8.58 (d, J=2.4 Hz, 1H), 7.98 (t, J=2.2 Hz, 1H), 7.44 (s, 1H),7.31 (d, J=9.3 Hz, 1H), 7.24 (d, J=8.4 Hz, 1H), 6.03-6.41 (m, 2H), 4.40(br, 1H), 4.02 (br, 1H), 3.62-3.66 (m, 1H), 3.31-3.53 (m, 2H), 2.84-2.88(m, 1H), 2.64-2.68 (m, 1H), 2.18-2.35 (m, 2H), 1.41 (d, J=5.7 Hz, 3H).LCMS (ESI, m/z): 441 [M+H]⁺.

Example 21: 5-Cyano-2-methylpyridin-3-yl(R)-2-methyl-4-(2-methyl-3-(trifluoromethyl)benzyl)piperazine-1-carboxylate

Step 1: Preparation of 5-hydroxy-6-methylnicotinonitrile

A 50-mL round-bottom flask was charged with 5-bromo-2-methylpyridin-3-ol(1.00 g, 5.32 mmol, 1.00 equiv), zinc cyanide (802 mg, 6.83 mmol, 1.30equiv), tetrakis(triphenylphosphane)palladium (615 mg, 0.532 mmol, 0.10equiv), and DMF (10 mL). The reaction was stirred overnight at 100° C.and quenched with water (10 mL). The resulting solution was extractedwith ethyl acetate (3×20 mL) and the organic layers were combined,washed with brine (2×5 mL), dried over anhydrous sodium sulfate,filtered, and concentrated under reduced pressure. The residue waschromatographed on a silica gel column to provide 250 mg (35% yield) of5-hydroxy-6-methylnicotinonitrile as a brown solid. LCMS (ESI, m/z): 135[M+H]⁺.

Step 2: Preparation of 5-cyano-2-methylpyridin-3-yl(R)-2-methyl-4-(2-methyl-3-(trifluoromethyl)benzyl)piperazine-1-carboxylate

A 25-mL round-bottom flask was charged with(R)-2-methyl-4-(2-methyl-3-(trifluoromethyl)benzyl)piperazine-1-carbonylchloride (240 mg, 0.716 mmol, 1.00 equiv, prepared as described inExample 20, Steps 1-3), 5-hydroxy-6-methylnicotinonitrile (115 mg, 0.858mmol, 1.20 equiv), 4-dimethylaminopyridine (17.5 mg, 0.143 mmol, 0.20equiv), DIPEA (277 mg, 2.15 mmol, 3.00 equiv), and tetrahydrofuran (5mL). The reaction was stirred overnight at 60° C. and quenched withwater (5 mL). The resulting solution was extracted with dichloromethane(3×20 mL) and the organic layers were combined, washed with brine (2×10mL), dried over anhydrous sodium sulfate, filtered, and concentratedunder reduced pressure. The crude product (300 mg) was purified bypreparative HPLC to afford 95.3 mg (31% yield) of5-cyano-2-methylpyridin-3-yl(R)-2-methyl-4-(2-methyl-3-(trifluoromethyl)benzyl)piperazine-1-carboxylateas a white solid. ¹H NMR (300 MHz, Chloroform-d) δ 8.61 (d, J=1.8 Hz,1H), 7.74 (d, J=1.8 Hz, 1H), 7.59 (d, J=7.8 Hz, 1H), 7.45 (d, J=7.5 Hz,1H), 7.22-7.26 (m, 1H), 4.41 (br, 1H), 3.98 (br, 1H), 3.49-3.59 (m, 2H),3.28-3.32 (m, 1H), 2.81-2.85 (m, 1H), 2.68-2.71 (m, 1H), 2.48-2.53 (m,6H), 2.34-2.38 (m, 1H), 2.12-2.21 (m, 1H), 1.38 (br, 3H). LCMS (ESI,m/z): 433 [M+H]⁺.

Examples 22-86

Examples 22-86 were prepared by similar procedures as described inExamples 1-21.

NMR (¹H NMR, 300 MHz or 400 MHz, MS Ex Name Structure Chloroform-d) [M +H]⁺ 22 5-(Trifluoromethyl) pyridin-3-yl 2-(3- isopropoxybenzyl)-2,7-diazaspiro[3,5] nonane-7- carboxylate

δ 8.62-8.71 (m, 2H), 7.77 (s, 1H), 7.21- 7.24 (m, 1H), 6.77- 6.85 (m,3H), 4.52- 4.60 (m, 1H), 3.59- 3.64 (m, 4H), 3.48 (br, 2H), 3.10-3.12(m, 4H), 1.74-1.85 (m, 4H), 1.34 (t, 464 J = 6.0 Hz, 6H). 235-(Trifluoromethyl) pyridin-3-yl 2-(3- (benzo[d]thiazol-2-yloxy)-5-chloro- benzyl)-2,7- diazaspiro[3.5] nonane-7- carboxylate

δ 8.72 (s, 1H), 8.62 (s, 1H), 7.69-7.76 (m, 3H), 7.39-7.44 (m, 1H),7.27-7.31 (m, 2H), 7.23 (s, 2H), 3.67 (s, 2H), 3.60 (br, 2H), 3.49 (br,2H), 3.11-3.13 589 (m, 4H), 1.86 (br, 4H). 24 5-(Trifluoromethyl)pyridin-3-yl 2-(3- chloro-5-isopro- poxybenzyl)-2,7- diazaspiro[3,5]nonane-7- carboxylate

δ 8.62-8.71 (m, 2H), 7.77 (s, 1H), 6.84 (s, 1H), 6.71- 6.76 (m, 2H),4.48- 4.56 (m, 1H), 3.57 (s, 4H), 3.49 (br, 2H), 3.08-3.10 (m, 4H), 1.85(br, 4H), 1.33 (t, J = 498 6.0 Hz, 6H). 25 5-(Trifluoromethyl)pyridin-3-yl 2-(3,5- dichlorophenoxy)- 7-azaspiro[3.5] nonane-7-carboxylate

δ 8.74 (s, 1H), 8.66 (s, 1H), 7.80 (s, 1H), 6.97 (s, 1H), 6.71 (s, 2H),4.65-4.74 (m, 1H), 3.52-3.67 (m, 4H), 2.46-2.53 (m, 2H), 2.00-2.06 (m,2H), 1.75 (s, 4H). 475 26 5-(Trifluoromethyl) pyridin-3-yl 2-(3-(pyrrolidine-1- carbonyl)phenoxy)- 7-azaspiro[3.5] nonane-7- carboxylate

δ 8.72 (s, 1H), 8.64 (s, 1H), 7.79 (s, 1H), 7.27-7.32 (m, 1H), 7.06-7.09(m, 1H), 6.95 (s, 1H), 6.86-6.88 (m, 1H), 4.71-4.80 (m, 1H), 3.48-3.67(m, 6H), 3.42-3.46 (m, 2H), 2.46-2.53 (m, 2H), 1.84-2.07 (m, 6H), 1.75(s, 4H). 504 27 5-(Trifluoromethyl) pyridin-3-yl 2-(2,5-dichlorophenoxy)- 7-azaspiro[3,5] nonane-7- carboxylate

δ 8.75 (s, 1H), 8.66 (s, 1H), 7.82 (s, 1H), 7.29-7.30 (m, 1H), 6.90-6.93(m, 1H), 6.73-6.74 (m, 1H), 4.72-4.81 (m, 1H), 3.51-3.70 (m, 4H),2.50-2.57 (m, 2H), 2.10-2.16 (m, 2H), 1.75-1.81 (m, 4H). 516 [M + H +MeCN]⁺ 28 5-(Trifluoromethyl) pyridin-3-yl 2- ([1,1′-biphenyl]-4-yloxy)-7- azaspiro[3.5] nonane-7- carboxylate

δ 8.67-8.76 (m, 2H), 7.82 (s, 1H), 7.54-7.62 (m, 4H), 7.43-7.48 (m, 2H),7.32-7.36 (m, 1H), 6.90-6.93 (m, 2H), 4.76-4.84 (m, 1H), 3.52-3.69 (m,4H), 2.50-2.57 (m, 2H), 2.02-2.13 (m, 2H), 1.76-1.80 (m, 4H). 483 295-(Trifluoromethyl) pyridin-3-yl 2-(3- ((4-chlorophenoxy)methyl)phenoxy)- 7-azaspiro[3.5] nonane-7- carboxylate

δ 8.75 (s, 1H), 8.66 (s, 1H), 7.81 (s, 1H), 7.29-7.34 (m, 1H), 7.24-7.26(m, 2H), 7.01 (d, J = 7.8 Hz, 1H), 6.88-6.94 (m, 3H), 6.77-6.80 (m, 1H),5.04 (s, 2H), 4.71- 4.80 (m, 1H), 3.50- 3.69 (m, 4H), 2.45- 2.52 (m,2H), 2.01- 547 2.08 (m, 2H), 1.76 (br, 4H). 30 5-(Trifluoromethyl)pyridin-3-yl 2-(4- (4-chlorophenoxy) benzyl)-2,7- diazaspiro[3.5]nonane-7- carboxylate

δ 8.72 (s, 1H), 8.62-8.65 (m, 1H), 7.76 (s, 1H), 7.23- 7.40 (m, 4H),6.92- 7.02 (m, 4H), 3.68- 3.75 (m, 2H), 3.40- 3.60 (m, 4H), 3.06- 3.29(m, 4H), 1.88 (br, 4H). 532 31 5-(Trifluoromethyl) pyridin-3-yl 2-(3-(4-chlorophenoxy) benzyl)-2,7- diazaspiro[3.5] nonane-7- carboxylate

δ 8.97 (s, 1H), 8.72 (s, 1H), 7.76 (s, 1H), 7.26-7.33 (m, 3H), 7.07-7.10(m, 1H), 6.88-6.97 (m, 4H), 3.70 (s, 2H), 3.49-3.60 (m, 4H), 3.00-3.28(m, 4H), 1.87 (br, 4H). 532 32 5-(Trifluoromethyl) pyridin-3-yl 2-(4-(pyridazin-4-yloxy) benzyl)-2,7- diazaspiro[3.5] nonane-7- carboxylate

δ 8.72 (s, 1H), 8.62 (s, 1H), 8.18- 8.21 (m, 1H), 8.03- 8.04 (m, 1H),7.73- 7.76 (m, 1H), 7.50- 7.66 (m, 4H), 6.59- 6.63 (m, 1H), 3.75- 3.83(m, 2H), 3.39- 3.61 (m, 4H), 3.15 (br, 4H), 1.88 (br, 4H). 500 335-(Trifluoromethyl) pyridin-3-yl 2-(3- (pyridazin-4-yloxy) benzyl)-2,7-diazaspiro[3.5] nonane-7- carboxylate

δ 8.72 (s, 1H), 8.62 (s, 1H), 8.23-8.26 (m, 1H), 8.04-8.05 (m, 1H), 7.76(s, 1H), 7.50-7.53 (m, 1H), 7.46-7.48 (m, 2H), 7.31-7.38 (m, 1H),6.60-6.64 (m, 1H), 3.77 (s, 2H), 3.36-3.61 (m, 4H), 3.17 (s, 4H), 1.89500 (br, 4H). 34 5-(Trifluoromethyl) pyridin-3-yl 2-(4-(pyrimidin-5-yloxy) benzyl)-2,7- diazaspiro[3.5] nonane-7- carboxylate

δ 8.97 (s, 1H), 8.72 (s, 1H), 8.63 (s, 1H), 8.47 (s, 2H), 7.77 (s, 1H),7.33-7.36 (m, 2H), 7.01-7.04 (m, 2H), 3.76 (s, 2H), 3.50- 3.69 (m, 4H),3.13- 3.15 (m, 4H), 1.88 (br, 4H). 500 35 5-(Trifluoromethyl)pyridin-3-yl 2-(3- (3,5-dichloro- phenoxy)benzyl)- 2,7-diazaspiro[3.5]nonane-7- carboxylate

δ 8.73 (s, 1H), 8.62 (d, J = 2.3 Hz, 1H), 7.78 (s, 1H), 7.27-7.37 (m,1H), 7.07-7.14 (m, 2H), 7.01 (s, 1H), 6.92-6.95 (m, 1H), 6.87 (d, J =1.8 566 Hz, 2H), 3.68 (s, 2H), 3.61 (br, 2H), 3.50 (br, 2H), 3.11 (br,4H), 1.86 (br, 4H). 36 5-Carbamoyl- pyridin-3-yl 2-(3,4-dichloro-benzyl)-2,8- diazaspiro[4.5] decane-8- carboxylate

δ 8.82 (s, 1H), 8.56 (d, J = 2.4 Hz, 1H), 7.95 (s, 1H), 7.61 (s, 1H),7.37-7.44 (m, 1H), 7.16-7.19 (m, 1H), 6.28 (br, 1H), 5.86 (br, 1H),3.45-3.69 (m, 6H), 2.62 (br, 2H), 2.43 (br, 2H), 1.66-1.90 (m, 6H). 46337 5-(Trifluoromethyl) pyridin-3-yl 2-(3- ((5-(trifluoromethyl)pyridin-2-yl)oxy) benzyl)-2,7- diazaspiro[3.5] nonane-7- carboxylate

δ 8.72 (s, 1H), 8.62 (d, J = 2.3 Hz, 1H), 8.45 (s, 1H), 7.82- 7.96 (m,1H), 7.77 (s, 1H), 7.32-7.48 (d, J = 15.6 Hz, 1H), 7.15-7.23 (d, J = 7.6Hz, 1H), 7.11 (s, 1H), 6.83- 7.09 (m, 2H), 3.70 567 (s, 2H), 3.40-3.65(m, 4H), 3.01-3.20 (d, J = 4.3 Hz, 4H), 1.73-1.96 (d, J = 3.2 Hz, 4H).38 5-(Trifluoromethyl) pyridin-3-yl 2-(3- ((5-(trifluoromethyl)pyridin-3-yl)oxy) benzyl)-2,7- diazaspiro[3.5] nonane-7- carboxylate

δ 8.72 (s, 1H), 8.62 (t, J = 4.6 Hz, 2H), 8.57 (d, J = 2.6 Hz, 1H), 7.77(s, 1H), 7.45 (s, 1H), 7.30- 7.40 (t, J = 15.7 Hz, 1H), 7.16 (d, J = 7.6Hz, 1H), 7.03 (d, J = 11.9 Hz, 1H), 6.87-7.00 (m, 567 1H), 3.67 (s, 2H),3.54-3.63 (t, J = 10.4 Hz, 2H), 3.38- 3.54 (t, J = 10.7 Hz, 2H),3.03-3.18 (m, 4H), 1.75-1.93 (m, 4H). 39 5-(Trifluoromethyl)pyridin-3-yl 2-(3- ((6-(trifluoromethyl) pyridin-3-yl)oxy) benzyl)-2,7-diazaspiro[3,5] nonane-7- carboxylate

δ 8.72 (s, 1H), 8.62 (d, J = 2.4 Hz, 1H), 8.46 (d, J = 2.6 Hz, 1H), 7.77(s, 1H), 7.64 (d, J = 8.6 Hz, 1H), 7.31-7.42 (m, 2H), 7.17 (d, J = 7.6Hz, 1H), 7.05 (s, 1H), 6.88-7.01 (d, J = 2.1 Hz, 567 1H), 3.40-3.70 (m,6H), 3.00-3.18 (m, 4H), 1.80-1.90 (m, 4H). 40 5-(Trifluoromethyl)pyridin-3-yl 2-(2- chloro-3-(3- chlorophenoxy) benzyl)-2,7-diazaspiro[3,5] nonane-7- carboxylate

δ 8.73 (s, 1H), 7.63 (d, J = 2.3 Hz, 1H), 7.78 (s, 1H), 7.22-7.34 (m,3H), 7.02-7.10 (m, 1H), 6.92-7.00 (m, 1H), 6.88-6.92 (m, 1H), 6.78-6.88(m, 1H), 3.83 (s, 2H), 3.43-3.72 (m, 4H), 3.22 (s, 4H), 1.76- 566 2.00(d, J = 4.6 Hz, 4H). 41 5-(Trifluoromethyl) pyridin-3-yl 2-(2-chloro-3-phenoxy- benzyl)-2,7- diazaspiro[3.5] nonane-7- carboxylate

δ 8.73 (s, 1H), 8.50-8.69 (d, J = 2.3 Hz, 1H), 7.77 (s, 1H), 7.29-7.40(m, 2H), 7.17-7.25 (m, 2H), 7.04-7.15 (m, 1H), 6.92-7.01 (m, 2H),6.82-6.92 (m, 1H), 3.83 (s, 2H), 3.59-3.72 (m, 2H), 3.43-3.59 (m, 2H),3.21 (s, 4H), 532 1.85-1.98 (m, 4H). 42 5-Fluoropyridin-3- yl4-(5-chloro-2- (trifluoromethyl) benzyl)piperazine- 1-carboxylate

δ 8.30-8.36 (m, 2H), 7.83 (s, 1H), 7.58 (d, J = 8.4 Hz, 1H), 7.34-7.38(m, 2H), 3.63-3.72 (m, 6H), 2.55-2.58 (m, 4H). 418 43 5-Cyanopyridin-3-yl 4-(5-chloro-2- (trifluoromethyl) benzyl)piperazine- 1-carboxylate

δ 8.66-8.72 (m, 2H), 7.83-7.86 (m, 2H), 7.59 (d, J = 8.7 Hz, 1H), 7.35(d, J = 8.4 Hz, 1H), 3.64-3.73 (m, 6H), 2.58 (t, J = 4.8 Hz, 4H). 425 445-(Trifluoromethyl) pyridin-3-yl 4-(5- chloro-2-(trifluoro-methyl)benzyl) piperazine-1- carboxylate

δ 8.65-8.73 (m, 2H), 7.80-7.84 (m, 2H), 7.58 (d, J = 8.4 Hz, 1H), 7.33-7.36 (m, 1H), 3.70- 3.76 (m, 4H), 3.64 (t, J = 4.8 Hz, 2H), 2.58 (t, J =5.1 Hz, 4H). 468 45 5-Fluoropyridin- 3-yl 4-(4- methoxy-3-(trifluoromethyl) benzyl)piperazine- 1-carboxylate

δ 8.34-8.35 (m, 1H), 8.29-8.30 (m, 1H), 7.54-7.55 (m, 1H), 7.46 (d, J =8.1 Hz, 1H), 7.26- 7.37 (m, 1H), 6.98 (d, J = 8.4 Hz, 1H), 3.91 (s, 3H),3.53-3.68 (m, 6H), 2.50 (br, 4H). 414 46 5-Fluoropyridin- 3-yl 4-((2,2-difluorobenzo[d] [1,3]dioxol-5-yl) methyl)piperazine- 1-carboxylate

δ 8.29-8.35 (m, 2H), 7.33-7.37 (m, 1H), 7.27 (s, 1H), 6.98-7.04 (m, 2H),3.54-3.68 (m, 6H), 2.49-2.52 (m, 4H). 396 47 5-Fluoropyridin- 3-yl4-(4-chloro- 3-ethoxybenzyl) piperazine-1- carboxylate

δ 8.35 (d, J = 2.4 Hz, 1H), 8.29 (d, J = 1.8 Hz, 1H), 7.27-7.37 (m, 2H),6.94 (d, J = 2.4 Hz, 1H), 6.83- 6.86 (m, 1H), 4.09- 4.16 (m, 2H), 3.57-3.69 (m, 4H), 3.51 394 (s, 2H), 2.48-2.51 (m, 4H), 1.48 (t, J = 6.9 Hz,3H). 48 5-Fluoropyridin- 3-yl 4-((4- (trifluoromethyl) pyridin-3-yl)methyl)piperazine- 1-carboxylate

δ 9.02 (s, 1H), 8.71 (d, J = 4.8 Hz, 1H), 8.30- 8.35 (m, 2H), 7.53 (d, J= 5.1 Hz, 1H), 7.34-7.38 (m, 1H), 3.60-3.76 (m, 6H), 2.58 (t, J = 4.8Hz, 4H). 385 49 5-Fluoropyridin- 3-yl 4-(4- isopropoxy-2- methylbenzyl)piperazine-1- carboxylate

δ 8.29-8.34 (m, 2H), 7.32-7.37 (m, 1H), 7.11 (d, J = 8.4 Hz, 1H), 6.65-6.73 (m, 2H), 4.49- 4.57 (m, 1H), 3.55- 3.64 (m, 4H), 3.45 (s, 2H),2.47-2.50 (m, 4H), 2.35 (s, 3H), 1.33 (d, J = 6.3 Hz, 6H). 388 505-Cyanopyridin- 3-yl 4-(3- (pyrimidin-2- yloxy)benzyl) piperazine-1-carboxylate

δ 8.71 (d, J = 1.8 Hz, 1H), 8.65 (d, J = 2.4 Hz, 1H), 8.58 (d, J = 4.8Hz, 2H), 7.83- 7.85 (m, 1H), 7.38- 7.44 (m, 1H), 7.22- 7.27 (m, 2H),7.12- 417 7.16 (m, 1H), 7.04- 7.07 (m, 1H), 3.58- 3.70 (m, 6H), 2.53-2.56 (m, 4H). 51 5-Carbamoyl- pyridin-3-yl 4- (3-carbamoyl-5-chlorobenzyl) piperazine-1- carboxylate

δ 8.89 (s, 1H), 8.56 (d, J = 2.7 Hz, 1H), 8.18 (br, 1H), 8.09 (br, 1H),8.02-8.03 (m, 1H), 7.80-7.83 (m, 2H), 7.68 (s, 1H), 7.53- 7.56 (m, 2H),3.60- 3.65 (m, 4H), 3.48 (br, 2H), 2.49-2.51 418 (m, 4H). 525-Acetamido- pyridin-3-yl 4- (4-chloro-3- isopropoxy- benzyl)piperazine-1-carboxylate

δ 8.11 (s, 3H), 7.95 (s, 1H), 7.25- 7.40 (m, 1H), 6.95 (s, 1H),6.73-6.92 (m, 1H), 4.45-4.72 (m, 1H), 3.26-3.93 (m, 6H), 2.58 (s, 4H),2.15 (s, 3H), 447 1.34-1.47 (m, 6H). 53 5-Carbamoyl- pyridin-3-yl 4-(4-chloro-3- isopropoxy- benzyl)piperazine- 1-carboxylate

δ 8.84 (s, 1H), 8.50-8.61 (m, 1H), 8.01 (s, 1H), 7.25- 7.34 (m, 1H),6.98 (s, 1H), 6.81-6.88 (m, 1H), 5.73-6.60 (m, 2H), 4.51-4.64 (m, 1H),3.51-3.74 433 (m, 4H), 3.48 (s, 2H), 2.41-2.73 (m, 4H), 1.24-1.51 (m,6H). 54 5-Carbamoyl- pyridin-3-yl (R)- 4-(3-carbamoyl- 4-chlorobenzyl)-2-methyl- piperazine-1- carboxylate

(Methanol-d₄) δ 8.82-8.95 (m, 1H), 8.52-8.62 (m, 1H), 8.01-8.17 (m, 1H),7.50-7.62 (m, 1H), 7.30-7.50 (m, 2H), 4.28-4.57 (m, 1H), 3.90-4.19 (m,1H), 3.48-3.67 (m, 2H), 3.35-3.48 (m, 1H), 432 2.84-2.97 (m, 1H),2.69-2.82 (m, 1H), 2.28-2.39 (m, 1H), 2.08-2.25 (m, 1H), 1.35-1.55 (m,3H). 55 5-Carbamoyl- pyridin-3-yl (S)- 4-(3-carbamoyl- 4-chlorobenzyl)-2-methyl- piperazine-1- carboxylate

(Methanol-d₄) δ 8.89-9.05 (m, 1H), 8.65-8.81 (m, 1H), 8.18-8.39 (m, 1H),7.49-7.85 (m, 3H), 4.18-4.77 (m, 4H), 3.33-3.88 (m, 5H), 1.28-1.78 (m,3H). 432 56 (R)-5-Carbamoyl- pyridin-3-yl 4-(4- chloro-3-isopro-poxybenzyl)-2- methylpiperazine- 1-carboxylate

(Methanol-d₄) δ 8.90 (m, 1H), 8.57 (m, 1H), 8.10 (m, 1H), 7.32 (m, 1H),7.13 (m, 1H), 6.91 (m, 1H), 4.65 (m, 1H), 4.27-4.54 (br, 1H), 3.86-4.18447 (br, 1H), 3.56-3.66 (m, 1H), 3.36-3.51 (m, 2H), 2.86-2.99 (d, J =11.4 Hz, 1H), 2.70-2.80 (d, J = 11.5 Hz, 1H), 2.12-2.34 (m, 2H),1.40-1.50 (m, 3H), 1.37 (m, 6H). 57 (S)-5-Carbamoyl- pyridin-3-yl 4-(4-chloro-3- isopropoxy- benzyl)-2- methylpiperazine- 1-carboxylate

(Methanol-d₄) δ 8.90 (m, 1H), 8.57 (m, 1H), 8.10 (m, 1H), 7.32 (m, 1H),7.13 (m, 1H), 6.91 (m, 1H), 4.65 (m, 1H), 4.27-4.54 447 (br, 1H), 3.86-4.18 (br, 1H), 3.56-3.66 (m, 1H), 3.36-3.51 (m, 2H), 2.86-2.99 (d, J =11.4 Hz, 1H), 2.70-2.80 (d, J = 11.5 Hz, 1H), 2.12-2.34 (m, 2H),1.40-1.50 (m, 3H), 1.37 (m, 6H). 58 (R)-5-Carbamoyl- pyridin-3-yl 2-methyl-4-(2- methyl-3- (trifluoromethyl) benzyl)piperazine-1-carboxylate

(Methanol-d₄) δ 8.90 (m, 1H), 8.57 (m, 1H), 8.10 (m, 1H), 7.49-7.70 (m,2H), 7.22-7.40 (m, 1H), 4.28-4.59 (br, 1H), 3.87- 4.19 (br, 1H), 3.60(s, 2H), 3.37- 3.50 (m, 1H), 2.80- 437 2.91 (m, 1H), 2.70- 2.80 (m, 1H),2.58 (s, 3H), 2.31-2.41 (m, 1H), 2.10-2.28 (m, 1H), 1.38 (s, 3H). 59(S)-5-Carbamoyl- pyridin-3-yl 2- methyl-4-(2- methyl-3-(trifluoromethyl) benzyl)piperazine- 1-carboxylate

(Methanol-d₄) δ 8.90 (m, 1H), 8.57 (m, 1H), 8.10 (m, 1H), 7.49-7.70 (m,2H), 7.22-7.40 (m, 1H), 4.28-4.59 (br, 1H), 3.87- 4.19 (br, 1H), 3.60(s, 2H), 3.37- 3.50 (m, 1H), 2.80- 437 2.91 (m, 1H), 2.70- 2.80 (m, 1H),2.58 (s, 3H), 2.31-2.41 (m, 1H), 2.10-2.28 (m, 1H), 1.38 (s, 3H). 605-Carbamoyl- pyridin-3-yl 4- (2-methyl-3- (trifluoromethyl)benzyl)piperazine- 1-carboxylate

δ 8.84 (s, 1H), 8.60 (s, 1H), 7.95- 8.04 (m, 1H), 7.51- 7.64 (m, 1H),7.37- 7.50 (m, 1H), 7.17- 7.26 (m, 1H), 5.79- 6.26 (m, 1H), 6.26- 6.67(m, 1H), 3.46- 3.79 (m, 6H), 2.45- 2.62 (m, 7H). 423 61 (S)-5-Amino-pyridin-3-yl 4- (4-chloro-3- isopropoxy- benzyl)-2- methylpiperazine-1-carboxylate

δ 8.89-8.99 (m, 1H), 8.82-8.86 (m, 1H), 7.28-7.33 (m, 1H), 6.98-7.18 (m,1H), 6.79-6.94 (m, 2H), 4.50-4.71 (m, 1H), 4.28-4.35 (m, 1H), 3.26-4.08(m, 6H), 2.58-3.11 (m, 419 2H), 2.07-2.41 (m, 2H), 1.35-1.45 (m, 9H). 62(R)-5-Amino- pyridin-3-yl 4- (4-chloro-3- isopropoxy- benzyl)-2-methylpiperazine- 1-carboxylate

δ 8.89-8.97 (m, 1H), 8.82-8.87 (m, 1H), 7.28-7.33 (m, 1H), 6.98-7.12 (m,1H), 6.79-6.88 (m, 2H), 4.50-4.71 (m, 1H), 4.28-4.35 (m, 1H), 3.18-4.15(m, 419 6H), 2.52-3.01 (m, 2H), 2.07-2.38 (m, 2H), 1.25-1.48 (m, 9H). 635-Carbamoyl- pyridin-3-yl 4- ((4-(trifluoro- methyl)pyridin-3-yl)methyl) piperazine-1- carboxylate

(Methanol-d₄) δ 9.04 (s, 1H), 8.85- 8.93 (m, 1H), 8.67- 8.76 (m, 1H),8.53- 8.62 (m, 1H), 8.04- 8.14 (m, 1H), 7.67- 7.77 (m, 1H), 3.82- 3.91(m, 2H), 3.70- 3.82 (m, 2H), 3.54- 3.66 (m, 2H), 2.57- 2.67 (m, 4H),1.88- 410 2.02 (m, 2H). 64 5-Carbamoyl- pyridin-3-yl 4- (4-chloro-3-ethoxyphenoxy) piperidine-1- carboxylate

(Methanol-d₄) δ 8.82-8.96 (m, 1H), 8.49-8.66 (m, 1H), 7.99-8.15 (m, 1H),7.12-7.28 (m, 1H), 6.48-6.72 (m, 2H), 4.53-4.72 (m, 1H), 3.51-4.18 (m,6H), 420 1.78-2.19 (m, 4H), 1.38-1.51 (m, 3H). 65 (R)-5- Carbamoyl-pyridin-3-yl 4- (3-chloro-5- (trifluoromethyl) benzyl)-2- methyl-piperazine-1- caiboxylate

(Methanol-d₄) δ 8.90-8.91 (m, 1H), 8.57-8.58 (m, 1H), 8.09-8.10 (m, 1H),7.62-7.72 (m, 3H), 4.25-4.61 (m, 1H), 3.83-4.25 (m, 1H), 3.67-3.77 (m,1H), 3.54-3.67 (m, 1H), 457 3.38-3.54 (m, 1H), 2.83-2.98 (m, 1H),2.62-2.80 (m, 1H), 2.18-2.45 (m, 2H), 1.30-1.56 (m, 3H). 66 (R)-5-Carbamoyl- pyridin-3-yl 4- (2-chloro-3- (trifluoromethyl) benzyl)-2-methyl- piperazine-1- carboxylate

(Methanol-d₄) δ 8.86-8.95 (m, 1H), 8.52-8.60 (m, 1H), 8.05-8.14 (m, 1H),7.82-7.93 (m, 1H), 7.69-7.78 (m, 1H), 7.44-7.56 (m, 1H), 4.24-4.69 (m,1H), 3.84-4.24 (m, 1H), 3.65-3.84 (br, 457 2H), 3.38-3.57 (m, 1H),2.85-2.98 (m, 1H), 2.70-2.85 (m, 1H), 2.38-2.54 (m, 1H), 2.17-2.38 (m,1H), 1.32-1.56 (m, 3H). 67 (R)-5-Cyano- pyridin-3-yl 4- (5-chloro-2-(trifluoromethyl) benzyl)-2- methyl- piperazine-1- carboxylate

δ 8.71 (s, 1H), 8.65 (s, 1H), 7.85 (s, 2H), 7.59 (d, J = 8.7 Hz, 1H),7.36 (d, J = 8.4 Hz, 1H), 4.41 (br, 1H), 4.00- 4.04 (m, 1H), 3.67 (s,2H), 3.43 (br, 1H), 2.85-2.88 (m, 1H), 2.67-2.71 (m, 439 1H), 2.40-2.42(m, 1H), 2.25-2.32 (m, 1H), 1.44-1.46 (m, 3H). 68 (R)-5-Cyano-pyridin-3-yl 2- methyl-4-(2- methyl-3- (trifluoromethyl) benzyl)piperazine-1- carboxylate

δ 8.70 (s, 1H), 8.64 (s, 1H), 7.84 (s, 1H), 7.59 (d, J = 7.8 Hz, 1H),7.44-7.46 (m, 1H), 7.23-7.27 (m, 1H), 4.40 (br, 1H), 3.96-4.00 (m, 1H),3.54 (s, 2H), 3.32 (br, 1H), 2.81- 2.84 (m, 1H), 2.67- 419 2.71 (m, 1H),2.51 (s, 3H), 2.35-2.38 (m, 1H), 2.13-2.21 (m, 1H), 1.38 (br, 3H). 69(R)-5-Fluoro- pyridin-3-yl 4-(5-chloro-2- (trifluoromethyl) benzyl)-2-methyl- piperazine-1- carboxylate

δ 8.35 (d, J = 2.4 Hz, 1H), 8.30 (s, 1H), 7.85 (br, 1H), 7.59 (d, J =8.7 Hz, 1H), 7.34- 7.37 (m, 2H), 4.41 (br, 1H), 4.01- 4.05 (m, 1H), 3.66(s, 2H), 3.49 (br, 1H), 2.84-2.88 (m, 1H), 2.70-2.76 (m, 432 1H),2.39-2.42 (m, 1H), 2.24-2.28 (m, 1H), 1.43-1.45 (m, 3H). 70(R)-5-Fluoro- pyridin-3-yl 2- methyl-4-((4- (trifluoromethyl)pyridin-3-yl) methyl) piperazine-1- carboxylate

δ 9.01 (s, 1H), 8.72 (d, J = 4.8 Hz, 1H), 8.35 (d, J = 2.4 Hz, 1H), 8.29(s, 1H), 7.54 (d, J = 5.1 Hz, 1H), 7.33-7.38 (m, 1H), 4.41 (br, 1H),3.99-4.09 (m, 1H), 3.71 (s, 2H), 3.49 (br, 1H), 2.82-2.85 (m, 1H), 3992.68-2.71 (m, 1H), 2.41-2.46 (m, 2H), 2.21-2.30 (m, 1H), 1.41-1.47 (m,3H). 71 (R)-5-Fluoro- pyridin-3-yl 2- methyl-4-(2- methyl-3-(trifluoromethyl) benzyl) piperazine-1- carboxylate

δ 8.34 (d, J = 2.4 Hz, 1H), 8.29 (s, 1H), 7.58 (d, J = 7.8 Hz, 1H), 7.45(d, J = 7.5 Hz, 1H), 7.33-7.38 (m, 1H), 7.22-7.30 (m, 1H), 4.39 (br,1H), 3.96-4.00 (m, 1H), 3.52-3.58 (m, 2H), 3.30 (br, 1H), 412 2.80-2.83(m, 1H), 2.65-2.69 (m, 1H), 2.51 (s, 3H), 2.20- 2.38 (m, 1H), 2.11- 2.19(m, 1H), 1.35- 1.37 (m, 3H). 72 5-fluoro-4- methylpyridin- 3-yl 4-(5-chloro-2- (trifluoromethyl) benzyl) piperazine-1- carboxylate

δ 8.29 (s, 1H), 8.22 (s, 1H), 7.84 (br, 1H), 7.59 (d, J = 8.4 Hz, 1H),7.34-7.36 (m, 1H), 3.76 (br, 2H), 3.71 (br, 2H), 3.63 (br, 2H),2.56-2.59 (m, 4H), 2.18 (s, 3H). 432 73 5-Cyano-4- methylpyridin- 3-yl4-(5- chloro-2- (trifluoromethyl) benzyl) piperazine-1- carboxylate

δ 8.66 (s, 1H), 8.54 (s, 1H), 7.83 (br, 1H), 7.59 (d, J = 8.4 Hz, 1H),7.34-7.37 (m, 1H), 3.72-3.76 (m, 4H), 3.64 (br, 2H), 2.58-2.65 (m, 4H),2.44 (s, 3H). 439 74 (R)-5- Carbamoyl- pyridin-3-yl 2-methyl-4-(3-(trifluoro- methoxy) benzyl) piperazine-1- carboxylate

δ 8.83 (d, J = 1.8 Hz, 1H), 8.58 (d, J = 2.7 Hz, 1H), 7.97 (t, J = 2.1Hz, 1H), 7.36 (t, J = 4.0 Hz, 1H), 7.26-7.28 (m, 2H), 7.12 (d, J = 7.8Hz, 1H), 6.36 (br, 1H), 5.90 (br, 1H), 4.38 (br, 1H), 3.99-4.03 (m, 4391H), 3.60-3.65 (m, 1H), 3.37-3.49 (m, 2H), 2.85-2.88 (m, 1H), 2.65-2.69(m, 1H), 2.15-2.31 (m, 2H), 1.40 (d, J = 6.0 Hz, 3H). 75 (R)-5-Cyano-pyridin-3-yl 2- methyl-4-(3- (trifluoro- methoxy) benzyl) piperazine-1-carboxylate

δ 8.64-8.71 (m, 2H), 7.84 (t, J = 2.1 Hz, 1H), 7.36 (t, J = 7.8 Hz, 1H),7.26-7.27 (m, 2H), 7.13 (d, J = 7.8 Hz, 1H), 4.37 (br, 1H), 3.98- 4.02(m, 1H), 3.60- 3.65 (m, 1H), 3.40- 3.49 (m, 2H), 2.86- 421 2.89 (m, 1H),2.66- 2.70 (m, 1H), 2.16- 2.31 (m, 2H), 1.40 (d, J = 5.7 Hz, 3H). 76(R)-5-Fluoro- pyridin-3-yl 2- methyl-4-(3- (trifluoro- methoxy) benzyl)piperazine-1- carboxylate

δ 8.29-8.34 (m, 2H), 7.33-7.38 (m, 2H), 7.26-7.27 (m, 2H), 7.12 (d, J =8.1 Hz, 1H), 4.38 (br, 1H), 3.98-4.03 (m, 1H), 3.60-3.64 (m, 1H),3.37-3.48 (m, 2H), 2.84-2.88 (m, 1H), 2.64-2.68 (m, 1H), 2.15-2.30 414(m, 2H), 1.39 (d, J = 6.6 Hz, 3H). 77 5-Amino- pyridin-3-yl(R)-2-methyl- 4-(3-(trifluoro- methoxy) benzyl) piperazine-1-carboxylate

δ 7.84-7.92 (m, 2H), 7.35 (t, J = 8.0 Hz, 1H), 7.26- 7.27 (m, 2H), 7.12(d, J = 7.8 Hz, 1H), 6.83 (t, J = 2.2 Hz, 1H), 4.37 (br, 1H), 3.92-4.02(m, 1H), 3.34-3.71 (m, 3H), 2.82-2.86 (m, 1H), 2.65-2.67 411 (m, 1H),2.13-2.29 (m, 2H), 1.40 (d, J = 6.9 Hz, 3H). 78 5-Cyano- pyridin-3-yl(R)-4-(3- fluoro-5- (trifluoromethyl) benzyl)-2- methyl- piperazine-1-carboxylate

δ 8.71 (s, 1H), 8.64 (s, 1H), 7.84 (t, J = 1.8 Hz, 1H), 7.43 (s, 1H),7.31 (d, J = 9.0 Hz, 1H), 7.23 (s, 1H), 4.39 (br, 1H), 4.00-4.04 (m,1H), 3.40-3.67 (m, 3H), 2.85-2.89 (m, 1H), 2.65-2.69 (m, 423 1H),2.19-2.36 (m, 2H), 1.42 (d, J = 6.3 Hz, 3H). 79 5-Fluoropyridin- 3-yl(R)-4- (3-fluoro-5- (trifluoromethyl) benzyl)-2- methyl- piperazine-1-carboxylate

δ 8.29-8.35 (m, 2H), 7.43 (s, 1H), 7.29-7.43 (m, 2H), 7.23 (s, 1H), 4.40(br, 1H), 4.00-4.04 (m, 1H), 3.61-3.66 (m, 1H), 3.39-3.53 (m, 2H),2.83-2.87 (m, 1H), 2.64-2.68 (m, 1H), 2.18-2.35 (m, 2H), 1.41 (d, 416 J= 6.6 Hz, 3H). 80 5-Amino- pyridin-3-yl (R)-4-(3-fluoro- 5-(trifluoro-methyl)benzyl)- 2-methyl- piperazine-1- carboxylate

δ 7.84-7.92 (m, 2H), 7.43 (s, 1H), 7.31 (d, J = 9.3 Hz, 1H), 7.24 (d, J= 8.4 Hz, 1H), 6.83 (t, J = 2.2 Hz, 1H), 4.39 (br, 1H), 3.99-4.04 (m,1H), 3.73 (br, 2H), 3.47-3.65 (m, 2H), 3.35 (br, 1H), 413 2.82-2.85 (m,1H), 2.62-2.66 (m, 1H), 2.16-2.33 (m, 2H), 1.39 (d, J = 6.9 Hz, 3H). 815-Amino- pyridin-3-yl (R)-2-methyl- 4-(2-methyl-3- (trifluoromethyl)benzyl) piperazine-1- carboxylate

δ 7.93 (d, J = 2.4 Hz, 1H), 7.84 (d, J = 2.1 Hz, 1H), 7.58 (d, J = 7.8Hz, 1H), 7.44 (d, J = 7.5 Hz, 1H), 7.23 (d, J = 7.5 Hz, 1H), 6.84 (t, J= 2.2 Hz, 1H), 4.39 (br, 1H), 409 3.95-3.99 (m, 1H), 3.46-3.74 (m, 4H),3.26 (br, 1H), 2.77-2.81 (m, 1H), 2.64-2.67 (m, 1H), 2.51 (s, 3H), 2.31-2.36 (m, 1H), 2.10- 2.18 (m, 1H), 1.34 (d, J = 6.9 Hz, 3H). 825-Carbamoyl- 4-methyl- pyridin-3-yl (R)-2-methyl- 4-(2-methyl-3-(trifluoromethyl) benzyl) piperazine-1- carboxylate

δ 8.48 (s, 1H), 8.38 (s, 1H), 7.59 (d, J = 7.8 Hz, 1H), 7.46 (d, J = 7.5Hz, 1H), 7.22-7.26 (m, 1H), 6.01-6.21 (m, 2H), 4.41-4.45 (m, 1H), 3.99(br, 1H), 3.47-3.59 (m, 2H), 451 3.28-3.31 (m, 1H), 2.80-2.84 (m, 1H),2.67-2.71 (m, 1H), 2.51 (s, 3H), 2.34- 2.38 (m, 4H), 2.13- 2.21 (m, 1H),1.38 (br, 3H). 83 5-Cyano-4- methyl- pyridin-3-yl (R)-2-methyl-4-(2-methyl-3- (trifluoromethyl) benzyl) piperazine-1- carboxylate

δ 8.65 (s, 1H), 8.53 (s, 1H), 7.59 (d, J = 7.8 Hz, 1H), 7.45 (d, J = 7.5Hz, 1H), 7.22-7.26 (m, 1H), 4.42-4.43 (m, 1H), 3.99 (br, 1H), 3.49-3.59(m, 2H), 3.25-3.39 (m, 1H), 2.82-2.85 (m, 1H), 433 2.68-2.72 (m, 1H),2.51 (s, 3H), 2.34- 2.43 (m, 4H), 2.13- 2.22 (m, 1H), 1.38 (br, 3H). 845-Cyano- pyridin-3-yl (R)-2-methyl- 4-(3- (pyrimidin-2- yloxy)benzyl)piperazine-1- carboxylate

δ 8.74 (d, J = 3.0 Hz, 1H), 8.66 (d, J = 3.0 Hz, 1H), 8.57-8.60 (m, 2H),7.85-7.86 (m, 1H), 7.42-7.48 (m, 1H), 7.28-7.33 (m, 2H), 7.08-7.08 (m,1H), 431 6.93-7.07 (m, 1H), 4.45 (br, 1H), 4.05 (br, 1H), 3.64-3.89 (m,3H), 2.83-3.12 (m, 2H), 2.32-2.42 (m, 2H), 1.47 (br, 3H). 855-Carbamoyl- pyridin-3-yl (R)-4-(3- chloro-5- fluorobenzyl)- 2-methyl-piperazine-1- carboxylate

δ 8.83 (s, 1H), 8.57 (s, 1H), 7.98 (s, 1H), 7.16 (s, 1H), 7.03-7.00 (m,2H), 6.49 (br, 1H), 6.12 (br, 1H), 4.40 (s, 1H), 4.01 (s, 1H), 3.55-3.52 (m, 1H), 3.46- 407 3.38 (m, 2H), 2.85- 2.83 (m, 1H), 2.69- 2.66 (m,1H), 2.32- 2.30 (m, 1H), 2.21- 2.15 (m, 1H), 1.41 (d, J = 3.2 Hz, 3H).86 5-Cyano- pyridin-3-yl (R)-4-(3- chloro-5- (pyrimidin-2-yloxy)benzyl)- 2-methyl- piperazine-1- carboxylate

(Methanol-d4) δ 8.80-8.73 (m, 1H), 8.72-8.60 (m, 1H), 8.60-8.58 (m, 2H),8.13-8.08 (m, 1H), 7.39-7.31 (m, 1H), 7.31-7.22 (m, 1H), 7.22-7.14 (m,2H), 4.61-4.23 (m, 1H), 487 [M + Na]⁺ 4.18-3.85 (m, 1H), 3.71-3.60 (m,1H), 3.60-3.49 (m, 1 H), 3.49-3.37 (m, 1H), 3.01-2.87 (m, 1H), 2.87-2.70(m, 1H), 2.41-2.28 (m, 1H), 2.28-2.11 (m, 1 H), 1.55-1.27 (m, 3 H).

II. Biological Evaluation

Compounds were tested to assess their MAGL and FAAH activity using thefollowing in vitro and in vivo assays.

In Vitro Competitive Activity-Based Protein Profiling.

Proteomes (mouse brain membrane fraction or cell lysates for mouseassays; human prefrontal cortex or cell membrane fractions for humanassays) (50 μL, 1.0 mg/mL total protein concentration) were preincubatedwith varying concentrations of inhibitors at 37° C. After 30 min, FP-Rhor HT-01 (1.0 μL, 50 μM in DMSO) was added and the mixture was incubatedfor another 30 min at 37° C. Reactions were quenched with SDS loadingbuffer (15 μL-4×) and run on SDS-PAGE. Following gel imaging, serinehydrolase activity was determined by measuring fluorescent intensity ofgel bands corresponding to MAGL and FAAH using ImageJ 1.43u software.IC₅₀ data from this assay is shown in Table 1.

Preparation of Mouse Brain Proteomes from Inhibitor Treated Mice.

Inhibitors were administered to wild-type C57Bl/6J by oral gavage in avehicle of polyethylene glycol. Each animal was sacrificed 4 h followingadministration and brain proteomes were prepared and analyzed accordingto previously established methods (See Niphakis, M. J., et al. (2011)ACS Chem. Neurosci. and Long, J. Z., et al. Nat. Chem. Biol. 5:37-44).

Compounds demonstrated activity in the assays described herein asindicated in Table 1.

TABLE 1 FAAH MAGL FAAH MAGL (human) (human) FAAH MAGL (mouse) (mouse) %inh. % inh. (human) (human) % inh. % inh. Ex 1 μM 1 μM IC₅₀ (μM) IC₅₀(μM) 5 mg/kg 5 mg/kg  1 A A *** ***  2 * **  3 A A *** ***  4 A A ****** A A  5 A A *** ***  6 A A *** ** A D  7 A A *** *** A C  8 ** ***  9** ** 10 *** *** 11 ** ** 12 B A 13 B A 14 B A 15 A A *** ** D D 16 A C17 A A ** *** 18 A A ** ** A A 19 A A *** * A D 20 A A *** *** A A 21 AC ** * 22 B C 23 A A *** *** 24 A A 25 A A ** *** 26 A A ** *** 27 A A*** *** 28 A A *** *** 29 A A *** ** 30 * ** 31 *** ** 32 A (10 μM) A(10 μM) 33 C B 34 * ** 35 A A 36 A A *** *** A C 37 A A 38 A A *** *** AD 39 A A ** ** 40 A A ** *** 41 A A 42 A A *** *** 43 A A *** *** 44 A A** ** 45 A A *** *** 46 A A 47 A A 48 A A *** ** 49 A A *** ** 50 A A ***** 51 A A ** * D D 52 A A ** *** A D 53 A A *** *** A B 54 A C (10 μM)55 A (50 M) B 56 A A ** ** 57 A (10 M) A 58 A A *** ** 59 B A 60 A A 61A (10 M) A 62 A C *** * 63 A A (10 μM) 64 A A *** *** A A 65 A A ** ** AA 66 A A *** *** 67 A A *** ** 68 A A *** *** 69 A A (10 μM) 70 A B (10μM) 71 A B *** ** A D 72 A A *** * 73 A A *** *** 74 A C *** ** A A 75 AA *** *** 76 A A (50 μM) *** * 77 A D 78 A A *** *** 79 A A (10 μM) ***** 80 A C (50 μM) 81 A D 82 A D 83 A A *** ** 84 A A ** *** 85 A A ***** A A 86 A A *** ** A A ***IC₅₀ is less than or equal to 100 μM; **IC₅₀is greater than 100 μM and less than 1 μM; *IC₅₀ is greater than orequal to 1 μM and less or equal to 10 μM. A = % inhibition is greaterthan or equal to 75%; B = % inhibition is greater than or equal to 50%and less than 75%; C = % inhibition is greater than or equal to 25% andless than 50%; D = % inhibition is greater than or equal to 0% and lessthan 25%.

What is claimed is:
 1. A method of treating a neurological disorder in asubject, the method comprising administering to the subject atherapeutically effective amount of a compound having the structure ofFormula (I):

wherein:

each R¹ is independently selected from halogen, —CN, C₁₋₆alkyl,C₂₋₆alkynyl, C₁₋₆alkyl-OR⁷, C₁₋₆haloalkyl, C₃₋₈cycloalkyl, —NR⁵R⁶,—C(O)NR⁵R⁶, —OR⁷, —SO₂R¹², —SF₅, —SR⁸, aryl, and heteroaryl, whereinaryl and heteroaryl are optionally substituted with one or two groupsindependently selected from halogen, C₁₋₆alkyl, C₁₋₆haloalkyl, and—C(O)NR⁸R⁹; or two adjacent R¹ form a heterocycloalkyl ring optionallysubstituted with one or two R¹¹; R² is C₁₋₆alkyl; R³ is selected fromhalogen, —CN, C₁₋₆alkyl, C₁₋₆haloalkyl, —NR⁸R⁹, —C(O)NR⁸R⁹, —NR⁸C(O)R⁹,and —NR⁹SO₂R⁸; R^(3a) is selected from halogen, C₁₋₆alkyl, andC₁₋₆haloalkyl; each R⁴ is independently selected from H and C₁₋₆alkyl;each R⁵ and R⁶ is independently selected from H, C₁₋₆alkyl, andC₃₋₈cycloalkyl; or R⁵ and R⁶, together with the nitrogen to which theyare attached, form a heterocycloalkyl optionally substituted with one ortwo R¹⁰; each R⁷ is independently selected from H, C₁₋₆alkyl,C₁₋₆alkyl-O—C₁₋₆alkyl, C₁₋₆haloalkyl, C₃₋₈cycloalkyl, heterocycloalkyl,aryl, and heteroaryl, wherein heterocycloalkyl, aryl, and heteroaryl areoptionally substituted with one or two groups independently selectedfrom halogen, C₁₋₆alkyl, and C₁₋₆haloalkyl; each R⁸ and R⁹ isindependently selected from H, C₁₋₆alkyl, C₃₋₈cycloalkyl, aryl, andheteroaryl; each R¹⁰ is independently selected from C₁₋₆alkyl,C₃₋₈cycloalkyl, C₁₋₆haloalkyl, halogen, oxo, —CN, —C(O)OR⁸, —C(O)R⁸,—C(O)NR⁸R⁹, —SO₂R⁸, —NR⁹C(O)R⁸, and —NR⁹SO₂R⁸; each R¹¹ is independentlyselected from halogen and C₁₋₆alkyl; each R¹² is independently selectedfrom C₁₋₆alkyl and C₃₋₈cycloalkyl; m is 0, 1, 2, 3, 4, or 5; n is 0, 1,2, or 3; p is 0 or 1; and q is 0 or 1; or a pharmaceutically acceptablesalt or solvate thereof.
 2. The method of claim 1, wherein R² is —CH₃.3. The method of claim 1, wherein


4. The method of claim 3, wherein m is 1 or
 2. 5. The method of claim 1,wherein R³ is C₁₋₆haloalkyl.
 6. The method of claim 5, wherein R³ is—CF₃.
 7. The method of claim 1, wherein R³ is halogen.
 8. The method ofclaim 1, wherein R³ is —C(O)NH₂.
 9. The method of claim 1, wherein R³ is—CN.
 10. The method of claim 1, wherein q is
 0. 11. The method of claim1, wherein q is
 1. 12. The method of claim 1, wherein each R¹ isindependently selected from halogen, C₁₋₆alkyl, C₁₋₆haloalkyl, and —OR⁷.13. The method of claim 12, wherein R⁷ is independently selected fromC₁₋₆alkyl, C₁₋₆haloalkyl, C₃₋₈cycloalkyl, aryl, and heteroaryl.
 14. Themethod of claim 13, wherein R⁷ is independently selected from C₁₋₆alkyland C₁₋₆haloalkyl.
 15. The method of claim 1, wherein each R⁴ is H. 16.The method of claim 1, wherein the compound having the structure ofFormula (I) is selected from:

or a pharmaceutically acceptable salt or solvate thereof.
 17. A methodof treating pain in a subject, the method comprising administering tothe subject a therapeutically effective amount of a compound having thestructure of Formula (I):

wherein:

each R¹ is independently selected from halogen, —CN, C₁₋₆alkyl,C₂₋₆alkynyl, C₁₋₆alkyl-OR⁷, C₁₋₆haloalkyl, C₃₋₈cycloalkyl, —NR⁵R⁶,—C(O)NR⁵R⁶, —OR⁷, —SO₂R¹², —SF₅, —SR⁸, aryl, and heteroaryl, whereinaryl and heteroaryl are optionally substituted with one or two groupsindependently selected from halogen, C₁₋₆alkyl, C₁₋₆haloalkyl, and—C(O)NR⁸R⁹; or two adjacent R¹ form a heterocycloalkyl ring optionallysubstituted with one or two R¹¹; R² is C₁₋₆alkyl; R³ is selected fromhalogen, —CN, C₁₋₆alkyl, C₁₋₆haloalkyl, —NR⁸R⁹, —C(O)NR⁸R⁹, —NR⁸C(O)R⁹,and —NR⁹SO₂R⁸; R^(3a) is selected from halogen, C₁₋₆alkyl, andC₁₋₆haloalkyl; each R⁴ is independently selected from H and C₁₋₆alkyl;each R⁵ and R⁶ is independently selected from H, C₁₋₆alkyl, andC₃₋₈cycloalkyl; or R⁵ and R⁶, together with the nitrogen to which theyare attached, form a heterocycloalkyl optionally substituted with one ortwo R¹⁰; each R⁷ is independently selected from H, C₁₋₆alkyl,C₁₋₆alkyl-O—C₁₋₆alkyl, C₁₋₆haloalkyl, C₃₋₈cycloalkyl, heterocycloalkyl,aryl, and heteroaryl, wherein heterocycloalkyl, aryl, and heteroaryl areoptionally substituted with one or two groups independently selectedfrom halogen, C₁₋₆alkyl, and C₁₋₆haloalkyl; each R⁸ and R⁹ isindependently selected from H, C₁₋₆alkyl, C₃₋₈cycloalkyl, aryl, andheteroaryl; each R¹⁰ is independently selected from C₁₋₆alkyl,C₃₋₈cycloalkyl, C₁₋₆haloalkyl, halogen, oxo, —CN, —C(O)OR⁸, —C(O)R⁸,—C(O)NR⁸R⁹, —SO₂R⁸, —NR⁹C(O)R⁸, and —NR⁹SO₂R⁸; each R¹¹ is independentlyselected from halogen and C₁₋₆alkyl; each R¹² is independently selectedfrom C₁₋₆alkyl and C₃₋₈cycloalkyl; m is 0, 1, 2, 3, 4, or 5; n is 0, 1,2, or 3; p is 0 or 1; and q is 0 or 1; or a pharmaceutically acceptablesalt or solvate thereof.
 18. The method of claim 17, wherein R² is —CH₃.19. The method of claim 17, wherein


20. The method of claim 19, wherein m is 1 or
 2. 21. The method of claim17, wherein R³ is C₁₋₆haloalkyl.
 22. The method of claim 21, wherein R³is —CF₃.
 23. The method of claim 17, wherein R³ is halogen.
 24. Themethod of claim 17, wherein R³ is —C(O)NH₂.
 25. The method of claim 17,wherein R³ is —CN.
 26. The method of claim 17, wherein q is
 0. 27. Themethod of claim 17, wherein q is
 1. 28. The method of claim 17, whereineach R¹ is independently selected from halogen, C₁₋₆alkyl,C₁₋₆haloalkyl, and —OR⁷.
 29. The method of claim 2, wherein R⁷ isindependently selected from C₁₋₆alkyl, C₁₋₆haloalkyl, C₃₋₈cycloalkyl,aryl, and heteroaryl.
 30. The method of claim 29, wherein R⁷ isindependently selected from C₁₋₆alkyl and C₁₋₆haloalkyl.
 31. The methodof claim 17, wherein each R⁴ is H.
 32. The method of claim 17, whereinthe compound having the structure of Formula (I) is selected from:

or a pharmaceutically acceptable salt or solvate thereof.